Method for treating post-traumatic stress disorder

ABSTRACT

The present disclosure provides compositions containing ketamine and methods of using those compositions for the treatment of post-traumatic stress disorder. Also provided herein is a pharmaceutical composition that comprises esketamine and a pharmaceutically acceptable carrier, excipient or diluent, for use in treatment of PTSD. In some aspects, the pharmaceutical composition is for intranasal or intravenous administration. In some aspects, the pharmaceutical composition is for use in a method of treating PTSD in a subject. In some aspects, the pharmaceutical composition is for use in a method of treating major depressive disorder in a subject that is co-morbid with the PTSD.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 61/811,681, filed Apr. 12, 2013, and 61/915,947, filed Dec. 13,2013. The entire disclosures of each of those provisional applicationsare considered part of, and are incorporated by reference in, thedisclosure of this application.

REFERENCE TO GOVERNMENT SUPPORT

This invention was made with government support under grantW81XWH-08-1-0602, awarded by the Department of the Army-USAMRAA. TheU.S. government has certain rights in the invention.

TECHNICAL FIELD

This disclosure relates to the methods and compositions for treatment ofpost-traumatic stress disorder.

BACKGROUND

Post-traumatic stress disorder (PTSD) is a prevalent and highlydebilitating psychiatric disorder that is notoriously difficult totreat. PTSD is characterized by flashbacks, emotional numbness, andinsomnia, and is associated with functional impairments, physical healthconcerns, and mental health comorbidities, such as depression, with sixfold higher risk of suicide. PTSD can result from a catastrophic andthreatening event, e.g., a natural disaster, wartime situation,accident, domestic abuse, or violent crime. Symptoms typically developwithin three months, but can emerge years after the initial trauma. Atsome point in their lifetimes, 5-8% of men and 10-14% of women,generally.

The treatment of PTSD is extremely challenging, and may include manyyears of individual and group therapy and medications such asantidepressants, anxiolytic drugs, β-adrenergic antagonists, opiates, orcortisol with variable results. Selective serotonin reuptake inhibitors(SSRIs) are currently recommended as the first-line pharmacotherapy.However, up to 40% of SSRI-treated PTSD patients do not respond and >70%never achieve full remission. The two SSRIs that are approved for PTSDby the United States Food and Drug Administration (FDA), paroxetine andsertraline, have modest effect sizes and limited efficacy in all threeclusters of illness: re-experiencing, avoidance and numbing, andhyperarousal.

PTSD is particularly prevalent among combat veterans. An estimated 17%of Operation Iraqi Freedom/Operation Enduring Freedom veterans willdevelop PTSD. A recent Veterans Affairs (VA) clinical trial of theFDA-approved drug, sertraline, failed to show efficacy in a group ofpatients with predominantly combat-related PTSD. The severity andsignificance of lack of SSRI efficacy, especially in light of theobserved relationship between trauma exposure and increased rates ofdisability, unemployment, and social assistance highlights the urgentneed for novel pharmacological interventions targeting the corepathophysiology of PTSD.

Ketamine is an antagonist of NMDA-type glutamate receptors. Ketamineexhibits anesthetic properties at high doses, e.g., doses of ˜2 mg/kg,and analgesic properties at subanesthetic doses. Ketamine is consideredsafe with minimal to moderate side effects.

There is a need in the art for improved methods for the treatment ofPTSD. The present disclosure describes compositions and methods of usingketamine to treat PTSD.

SUMMARY

The present disclosure provides therapeutic agents and methods fortreating PTSD.

In certain aspects, a method of treating post-traumatic stress disorder(PTSD) as provided herein includes treating a human individual sufferingfrom PTSD with a therapeutically effective amount of ketamine. In someaspects, the effective amount of ketamine is a dose of about 0.01 toabout 2.0 mg of ketamine per kilogram of body weight of the patient(mg/kg) to treat PTSD. In some aspects, the dose is about 0.05 to about0.5 mg/kg of ketamine. In some aspects, the dose is less than about 0.5mg/kg, less that about 0.4 mg/kg or less than about 0.3 mg/kg ofketamine. In some aspects, the effective amount of ketamine is a dose inthe range of from about 0.01 mg/kg to about 2.0 mg/kg. In some aspects,the effective amount of ketamine is a dose in the range of from about0.01 mg/kg to about 1.5 mg/kg. In some aspects, the effective amount ofketamine is a dose in the range of from about 0.01 mg/kg to about 1mg/kg. In some aspects, the effective amount of ketamine is a dose inthe range of from about 0.01 mg/kg to about 0.75 mg/kg. In some aspects,the effective amount of ketamine is a dose in the range of from about0.75 mg/kg to about 1.5 mg/kg. In some aspects, the effective amount ofketamine is a dose in the range of from about 0.5 mg/kg to about 1.2mg/kg. In some aspects, the effective amount of ketamine is a dose inthe range of from about 0.05 mg/kg to about 0.5 mg/kg. In some aspects,the effective amount of ketamine is a dose of about 0.2 mg/kg or in anamount of about 0.4 mg/kg.

In some aspects, the total dose of ketamine is about 25 mg. In someaspects, the total dose of ketamine is about 50 mg. In some aspects, thetotal dose of ketamine is about 75 mg. In some aspects, the total doseof ketamine is about 100 mg. In some aspects, the total dose of ketamineis about 1.1 mg/kg. In some aspects, the total dose of ketamine is about1.2 mg/kg 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8mg/kg, 1.9 mg/kg, or 2.0 mg/kg.

In some aspects, the therapeutically effective amount of ketamine is asub-anesthetic amount of ketamine for the individual. In some aspects,the therapeutically effective amount of ketamine is a sub-analgesicamount of ketamine for the individual. In some aspects, the individualis treated with ketamine via intravenous or intranasal administration.In some aspects, the individual is treated intranasally with ketamine,substantially only via the nasal respiratory epithelium, compared totreatment via the nasal olfactory epithelium. In some aspects, theindividual is treated intranasally with ketamine, substantially only viathe nasal olfactory epithelium, compared to treatment via the nasalrespiratory epithelium. In some aspects, the individual is treated witha single dose of the therapeutically effective amount of ketamine. Insome aspects, the individual is treated with multiple doses of thetherapeutically effective amount of ketamine. In some aspects, theindividual is treated with at least one dose of the therapeuticallyeffective amount of ketamine per week for a period of two or more weeks.

In some aspects, the above methods for treating a human individualsuffering from PTSD further include administering a second agent totreat the PTSD. In some aspects, the second active agent is ananti-depressant. In some aspects, the second active agent is paroxetine,sertraline, lithium, riluzole, prazosin, lamotrigine, or ifenprodil. Insome aspects, the second agent is used as adjunctive therapy to ketaminetreatment. In some aspects, the treatment includes a phase whereintreatment with the second agent takes place after treatment withketamine as ceased. In some aspects, the treatment includes a phasewhere treatment with ketamine and treatment with the second agentoverlap.

Also provided herein is a method of dosing treatment of PTSD withketamine. The method can include treating an individual suffering fromPTSD with one or more doses comprising a first amount of ketamine totreat PTSD and thereafter treating the individual with one or more dosescomprising a second amount of ketamine to maintain treatment of thePTSD, where the second amount of ketamine is lower than the first amountof ketamine. In some aspects, the second amount of ketamine is an amountthat is at most one-half, one-quarter, or one-tenth the amount of thefirst amount of ketamine. In some aspects, the method further includestreating major depressive disorder that is co-morbid with the PTSD. Insome aspects, the ketamine is administered in a composition comprising apharmaceutically acceptable carrier, excipient or diluent.

Also provided herein is a pharmaceutical composition that comprisesketamine and a pharmaceutically acceptable carrier, excipient ordiluent, for use in treatment of PTSD. In some aspects, thepharmaceutical composition is for intranasal or intravenousadministration. In some aspects, the pharmaceutical composition is foruse in a method of treating PTSD in a subject. In some aspects, thepharmaceutical composition is for use in a method of treating majordepressive disorder in a subject that is co-morbid with the PTSD.

In any of the above aspects, the ketamine can be esketamine. Thus, alsoprovided is a method of treating PTSD comprising administering to apatient in need of such treatment an effective amount for treating PTSDof ketamine or esketamine.

Also provided herein is a method of treating PTSD that includes treatinga human individual suffering from PTSD with a therapeutically effectiveamount of esketamine. In some aspects, the esketamine is administered inan amount in the range of from about 0.01 mg/kg to about 2.0 mg/kg. Insome aspects, the esketamine is administered in an amount in the rangeof from about 0.01 mg/kg to about 1.5 mg/kg. In some aspects, theesketamine is administered in an amount in the range of from about 0.01mg/kg to about 1 mg/kg. In some aspects, the esketamine is administeredin an amount in the range of from about 0.01 mg/kg to about 0.75 mg/kg.In some aspects, the esketamine is administered in an amount in therange of from about 0.75 mg/kg to about 1.5 mg/kg. In some aspects, theesketamine is administered in an amount in the range of from about 0.5mg/kg to about 1.2 mg/kg. In some aspects, the esketamine isadministered in an amount in the range of from about 0.05 mg/kg to about0.5 mg/kg. In some aspects, the esketamine is administered in an amountof about 0.2 mg/kg or in an amount of about 0.4 mg/kg.

In some aspects, the total dose of esketamine is about 25 mg. In someaspects, the total dose of esketamine is about 50 mg. In some aspects,the total dose of esketamine is about 75 mg. In some aspects, the totaldose of esketamine is about 100 mg. In some aspects, the total dose ofesketamine is about 1.1 mg/kg. In some aspects, the total dose ofesketamine is about 1.2 mg/kg 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, or 2.0 mg/kg.

In some aspects, the esketamine is administered intravenously. In someaspects, the esketamine is administered intranasally. In some aspects,the method of treating PTSD further includes treating major depressivedisorder that is co-morbid with the PTSD.

Also provided herein is a pharmaceutical composition that comprisesesketamine and a pharmaceutically acceptable carrier, excipient ordiluent, for use in treatment of PTSD. In some aspects, thepharmaceutical composition is for intranasal or intravenousadministration. In some aspects, the pharmaceutical composition is foruse in a method of treating PTSD in a subject. In some aspects, thepharmaceutical composition is for use in a method of treating majordepressive disorder in a subject that is co-morbid with the PTSD.

DESCRIPTION OF DRAWINGS

FIGS. 1A-1C contain graphs quantifying the change in the Impact of EventScale-Revised (IES-R) total score (FIG. 1A), mean IES-R subscale score(FIG. 1B), and the Montgomery-Asberg Depression Rating Scale (MADRS)score over 1 week following the first infusion of ketamine or midazolam.Error bars indicate standard errors (n=41).

FIGS. 2A-2C contain line graphs quantifying the change in the BriefPsychiatric Rating Scale (BPRS) Positive Symptoms subscale score, theClinician-Administered Dissociative States Scale (CADSS) score, and theYoung Mania Rating Scale (YMRS) item 1 score over 1 week after the firstinfusion of ketamine or midazolam (n=41). Error bars represent standarderrors.).

DETAILED DESCRIPTION

Key in the pathophysiology of PTSD is dysregulation of the stressresponse in response to traumatic events such as those encountered inchronic combat situations and extended deployment. The role of the humanstress system is to respond to a stressor by activating not only thehypothalamic-pituitary-adrenocortical (HPA) axis, but also a complexcascade of reactions mediated by many other neurotransmitters, includingexcitatory and inhibitory amino acid neurotransmitters such asglutamate. While this response helps the species adapt and cope when thestressor is acute and short-lived, it may have pathological consequenceswhen the stressor is chronic and overwhelming.

Preclinical studies have found that chronic stress is associated withextracellular glutamate accumulation, which results in sensitization ofcorticolimbic glutamatergic pathways and potentiation of the behavioralstress response. Persistent hyperactivity of this system may alsocontribute to glutamate-mediated excitotoxicity leading to hippocampalatrophy and, ultimately, memory disturbances, which are common in PTSDand other stress-related conditions such as major depression.Dysregulation of glutamatergic pathways has been hypothesized to play acentral role in producing the core symptoms of PTSD, heightened stresssensitivity (startle), tension and anxiety, memory disturbances, anddissociation.

Recent evidence that conventional antidepressants have broad effects onspecific glutamate receptors also suggests an approach to develop anovel class of drugs which may enhance neuronal plasticity and cellularresilience. Antagonists at the glutamatergic NMDA receptor mayconstitute such a novel class of drugs. Ketamine, a well-knownFDA-approved analgesic and anesthetic medication which in glutamatergicpathways works as a high-affinity NMDA antagonist. An abundance ofpreclinical data suggests that ketamine also has antidepressant andanxiolytic properties.

As disclosed herein, ketamine is useful for the treatment of PTSD.

DEFINITIONS

The following definitions are provided for clarity and illustrativepurposes only, and are not intended to limit the scope of the presentdisclosure.

The term “intranasal administration” in all its grammatical forms refersto administration of a drug through the nasal mucous membrane andthrough the nose-brain pathway directly into the cerebrospinal fluid.

The term “aerosol” refers to suspension in the air. In particular,aerosol refers to the particularization or atomization of a formulationdisclosed herein and its suspension in the air. Thus, an aerosolformulation is a formulation comprising ketamine for intranasaladministration.

Generally, “treating” or “treatment” of a state, disorder or conditionincludes: (1) preventing or delaying the appearance of clinical orsub-clinical symptoms of the state, disorder or condition developing ina mammal that may be afflicted with or predisposed to the state,disorder or condition but does not yet experience or display clinical orsubclinical symptoms of the state, disorder or condition; or (2)inhibiting the state, disorder or condition, i.e., arresting, reducingor delaying the development of the disorder or a relapse thereof (incase of maintenance treatment) or at least one clinical or sub-clinicalsymptom thereof; or (3) relieving the disorder, i.e., causing regressionof the state, disorder or condition or at least one of its clinical orsub-clinical symptoms. The benefit to a subject to be treated is eitherstatistically significant or at least perceptible to the patient or tothe physician.

The phrase “pharmaceutically acceptable” refers to molecular entitiesand compositions that are generally believed to be physiologicallytolerable and do not typically produce an allergic or similar untowardreaction, such as gastric upset, dizziness and the like, whenadministered to a human. The term “pharmaceutically acceptablederivative” refers to any pharmaceutically acceptable salt, solvate orprodrug, e.g. ester, of a compound which upon administration to therecipient is capable of providing (directly or indirectly) a compound oran active metabolite or residue thereof. Such derivatives arerecognizable to those skilled in the art, without undue experimentation.Derivatives are described, for example, in Burger's Medicinal Chemistryand Drug Discovery, 5th Edition, Vol 1: Principles and Practice, whichis incorporated herein by reference to the extent of teaching suchderivatives. Preferred pharmaceutically acceptable derivatives includesalts, solvates, esters, carbamates, and phosphate esters. Particularlypreferred pharmaceutically acceptable derivatives are salts, solvates,and esters. Most preferred pharmaceutically acceptable derivatives aresalts and esters.

A “therapeutically effective amount” of a drug is an amount effective todemonstrate a desired activity of the drug. A therapeutically effectiveamount of ketamine is an amount effective to alleviate, i.e., noticeablyreduce, one or more of the symptoms of a PTSD patient. A“therapeutically effective amount” will vary depending on the compound,the disorder and its severity and the age, weight, physical conditionand responsiveness of the mammal to be treated.

The term “combination therapy” means the treatment of a subject in needof treatment with a certain composition or drug in which the subject istreated or given one or more other compositions or drugs for thedisorder or condition in conjunction with the first and/or inconjunction with one or more other therapies, such as, e.g., a therapysuch as a therapy comprising administering an anti-depressant agent.Combination therapy can be sequential therapy wherein the patient istreated first with one treatment modality (e.g., drug or therapy), andthen the other (e.g., drug or therapy), and so on, or one more drugsand/or therapies can be administered simultaneously. In either case,these drugs and/or therapies are said to be “coadministered.” It is tobe understood that “coadministered” does not necessarily mean that thedrugs and/or therapies are administered in a combined form (i.e., theymay be administered separately or together to the same or differentsites at the same or different times).

The details of one or more embodiments of the present disclosure are setforth in the description and claims below. The present disclosure ismeant to be descriptive and illustrative and is not intended to limitthe scope of the presently disclosed invention.

Overview

The present disclosure describes compositions and methods for thetreatment of PTSD.

As described herein, ketamine can be used to effectively treatpost-traumatic stress disorder (PTSD). Exemplary dosages of ketamine,e.g., intravenous and intranasal delivery of ketamine, are describedbelow. Particularly preferred dosages of ketamine for the treatment ofPTSD are subanesthetic doses of ketamine, e.g., a range from about 0.01mg/kg to about 2.0 mg/kg, delivered, e.g., intranasally.

Ketamine ((2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone) is ageneral anesthetic used by anesthesiologists, veterinarians, andresearchers. Pharmacologically, ketamine is a noncompetitive NMDAreceptor (NMDAR) antagonist. More specifically, ketamine binds to theallosteric site of the NMDA receptor, effectively inhibiting itschannel. At high, fully anesthetic level doses, ketamine has also beenfound to bind to μ-opioid receptors type 2 in cultured humanneuroblastoma cells—however, without agonist activity—and to sigmareceptors in rats. Also, ketamine interacts with muscarinic receptors,descending monoaminergic pain pathways and voltage-gated calciumchannels.

Ketamine is a chiral compound. The S(+) and R(−) stereoisomers bind NMDAreceptors with different affinities: Ki=3200 and 1100 nM, respectively.Vranken et al. studied the use of an iontophoretic patch (a mechanism ofdelivery in which the electrically charged drug is transmitted by pulsesof galvanic current) in 33 men and women in an investigation thatstudied the use of an iontophoretic patch to deliver ketamine for thetreatment of intractable central neuropathic pain. S(+)-ketamine (alsoreferred to as “(S)-ketamine” or “esketamine”) was found to be two timesmore potent than racemic mixture of ketamine. Most pharmaceuticalpreparations of ketamine are racemic; however, some brands reportedlyhave (mostly undocumented) differences in enantiomeric proportions. Themore active (S)-ketamine enantiomer is available for medical use underthe brand name Ketanest S. Its hydrochloride salt is sold as Ketanest,Ketaset, and Ketalar. See, Paul et al., “Comparison of racemic ketamineand S-ketamine in treatment-resistant major depression: report of twocases”, World J. of Bio. Psych., 2009, pp 241-244, Vol. 10(3) describetwo cases studies in which patients with a history of recurrent majordepression were treated with intravenous infusion of ketamine andS-ketamine; Paskalis et al., “Oral Administration of the NMDA ReceptorAntagonist S-Ketamine as Add-on Therapy of Depression: A Case Series”,Pharmacopsychiatry, 2010, pp 33-35, Vol. 40 present four case studieswhere depressed patients received 1 0.25 mg/kg oral S-ketamine as add-onto standard antidepressant therapy; Noppers et al., “Absence oflong-term analgesic effect from a short-term S-ketamine infusion onfibromyalgia pain: A randomized, prospective, double blind, activeplacebo-controlled trial”, Eur. J. of Pain., 2011, article in press,describe a trial assessing the analgesic efficacy of S-(+)-ketamine onfibromyalgia pain; Matthews et al., “Ketamine for Treatment-ResistantUnipolar Depression”, CNS Drugs, 2012, pp 1-16, provide a review ofemerging literature on ketamine and a review of the pharmacology of bothketamine and S-ketamine; and International Patent Publication No.WO2013138322. As used herein, “ketamine” includes preparations ofketamine that contain a racemic mixture of S(+) and R(−) stereoisomersof ketamine, preparations that contain differences in the enantiomericproportions of the S(+) and R(−) stereoisomers, and preparations thatcontain only one of the enantiomers (e.g., only S(+) ketamine or onlyR(−) ketamine.

Intranasal administration of ketamine and midazolam to achieve sedationfor ophthalmic surgery, and to induce anesthesia prior to electivesurgery in healthy children has been reported. Ketamine has also beenknown to have analgesic properties; analgesia can be achieved withsubanesthetic doses of ketamine. The drug is administered by variousroutes, including intravenous (i.v. or IV), intranasal (i.n. or IN),intramuscular (i.m. or IM), caudal, intrathecal, and subcutaneous(s.c.).

Subcutaneous administration of ketamine has been used to treat painfollowing surgery and associated with terminal cancer. Ketaminehydrochloride administered via a subcutaneous cannula was reported tosuccessfully treat phantom limb pain.

Intravenous administration of ketamine has been used for the rapidtreatment of treatment-resistant major depression. A 0.5 mg/kgintravenous infusion given over 40 minutes resulted in improvements indepression within 2 hours post-injection; and continued for up to 1week. There were no serious adverse events. Zarate et al., Am JPsychiatry, 2006, 163:153-5. Intranasal (IN) ketamine plasma levels usedfor treatment of pain are 3-4 fold lower than the intravenous (IV)ketamine studies in depression. The slow infusion of ketamine producesgradually increasing plasma levels during the infusion period.

A typical ketamine dose for induction of anesthesia for surgicalprocedures is between 1.0-2.0 mg/kg, with additional ketamine used tosustain anesthesia. In anesthesia, the target ketamine blood level isreached with ketamine bolus doses between 0.2-0.26 mg/kg over 1 min. Thedose for ketamine plasma levels to produce antidepressant responses asopposed to the levels needed to produce anesthesia is in the range of0.5 mg/kg over 40 min. The reports of dissociation in pain studies weresignificantly lower than the IV studies in major depressive disorderbecause the ketamine levels achieved intranasally in these studies weremuch lower. The intranasal dose used for pain (50 mg) is roughlyequivalent to 0.1 mg/kg i.v. of ketamine.

The present invention is directed to methods and compositions fortreating PTSD using ketamine. Then present invention also encompassesmethods and compositions for treating PTSD using esketamine. Thetreatments disclosed herein may be administered alone or may besupplemented with other antidepressant therapies, as described below.

Ketamine is an inexpensive, readily available drug, with minor adverseside effects. Thus, the invention contemplates additional savings to theoverburdened health care system. Intranasal administration of this agentis rapid, allowing for fast action of the drug, and easily accomplishedby a non-medically trained patient.

In some aspects, the PTSD-alleviating dose of ketamine is approximately0.01 to approximately 3 mg/kg of body weight, approximately 0.01 toapproximately 2 mg/kg of body weight, approximately 0.01 toapproximately 1.5 mg/kg of body weight, approximately 0.05 toapproximately 1.4 mg/kg of body weight, approximately 0.05 toapproximately 1.3 mg/kg of body weight, approximately 0.05 toapproximately 1.2 mg/kg of body weight, approximately 0.05 toapproximately 1.1 mg/kg of body weight, approximately 0.01 toapproximately 1 mg/kg of body weight, or approximately 0.05 toapproximately 0.7 mg/kg of body weight.

In some aspects, the PTSD-alleviating dose of esketamine isapproximately 0.01 to approximately 3 mg/kg of body weight,approximately 0.01 to approximately 2 mg/kg of body weight,approximately 0.01 to approximately 1.5 mg/kg of body weight,approximately 0.05 to approximately 1.4 mg/kg of body weight,approximately 0.05 to approximately 1.3 mg/kg of body weight,approximately 0.05 to approximately 1.2 mg/kg of body weight,approximately 0.05 to approximately 1.1 mg/kg of body weight,approximately 0.01 to approximately 1 mg/kg of body weight, orapproximately 0.05 to approximately 0.7 mg/kg of body weight.

In some aspects, the PTSD-alleviating dose of ketamine is approximately0.01 mg to about 1000 mg, or any amount or range therein, preferablyfrom about 0.01 mg to about 500 mg, or any amount or range therein,preferably from about 0.1 mg to about 250 mg, or any amount or rangetherein. In another aspect, the PTSD-alleviating dose of ketamine is,e.g., 0.01 mg, 0.025 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 25mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 90 mg, 95 mg, 100mg, 150 mg, 200 mg, 250 mg, or 500 mg.

In one aspect, the PTSD-alleviating dose of esketamine is approximately0.01 mg to about 1000 mg, or any amount or range therein, preferablyfrom about 0.01 mg to about 500 mg, or any amount or range therein,preferably from about 0.1 mg to about 250 mg, or any amount or rangetherein. In another aspect, the PTSD-alleviating dose of esketamine is,e.g., 0.01 mg, 0.025 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 25mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 90 mg, 95 mg, 100mg, 150 mg, 200 mg, 250 mg, or 500 mg.

Ketamine has been used in the treatment of breakthrough pain (BTP) inchronic pain patients. In such patients, 10-50 mg of ketamine has beenadministered through intranasal administration in incremental 10 mgdoses, every 90 seconds. The effect of that intranasal administration ofketamine was that there was a lower BTP in patients that receivedintranasal ketamine as opposed to placebo. There were very few sideeffects with such administration.

Formulations, Dosage Forms and Modes of Administration

While it is possible to use a composition disclosed herein (e.g., acomposition comprising ketamine for therapy as is, it may be preferableto formulate the composition in a pharmaceutical formulation, e.g., inadmixture with a suitable pharmaceutical excipient, diluent, or carrierselected with regard to the intended route of administration andstandard pharmaceutical practice. Suitable carriers and theirformulations are described in Remington: The Science and Practice ofPharmacy, 21^(st) ed., 2005, Lippincott, Williams & Wilkins, Phila., Pa.Accordingly, in one aspect, a pharmaceutical composition or formulationcomprises at least one active composition of ketamine in associationwith a pharmaceutically acceptable excipient, diluent, and/or carrier.The excipient, diluent and/or carrier must be “acceptable” in the senseof being compatible with the other ingredients of the formulation andnot deleterious to the recipient thereof.

For in vivo administration to humans, the compositions can be formulatedaccording to known methods used to prepare pharmaceutically usefulcompositions. Compositions may be designed to be short-acting,fast-releasing, long-acting, or sustained-releasing. Thus,pharmaceutical formulations may also be formulated for controlledrelease or for slow release.

When formulated in a pharmaceutical composition or formulation, ketaminecan be admixed with a pharmaceutically acceptable carrier or excipient.The term “carrier” refers to a diluent, adjuvant, excipient, or vehiclewith which the compound is administered. Such pharmaceutical carrierscan be sterile liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. Water or aqueoussolution saline solutions and aqueous dextrose and glycerol solutionsare preferably employed as carriers, particularly for injectablesolutions. Other exemplary carriers include, but are not limited to, anyof a number of standard pharmaceutical carriers such as sterilephosphate buffered saline solutions, bacteriostatic water, and the like.A variety of aqueous carriers may be used, e.g., water, buffered water,0.4% saline, 0.3% glycine and the like.

The compositions and formulations described herein may be foradministration by oral (solid or liquid), parenteral (intramuscular,intraperitoneal, intravenous (IV) or subcutaneous injection),transdermal (either passively or using ionophoresis or electroporation),transmucosal (nasal, intranasal, vaginal, rectal, or sublingual), orinhalation routes of administration, or using bioerodible inserts andcan be formulated in dosage forms appropriate for each route ofadministration. The most suitable route in any given case will depend onthe particular host, and nature and severity of the conditions for whichthe active ingredient is being administered. The compositions may beconveniently presented in unit dosage form and prepared by any of themethods well known in the art of pharmacy, and using well known carriersand excipients.

In general, preparations according to this invention include sterileaqueous or non-aqueous solutions, suspensions, or emulsions. Examples ofnon-aqueous solvents or vehicles are propylene glycol, polyethyleneglycol, vegetable oils, such as olive oil and corn oil, gelatin, andinjectable organic esters such as ethyl oleate. Such dosage forms mayalso optionally contain adjuvants, preserving, wetting, emulsifying, anddispersing agents. The pharmaceutical compositions may be sterilized by,for example, filtration through a bacteria retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured using sterile water, or some other sterile injectablemedium, immediately before use.

Intravenous Administration

A preferred route of administration of ketamine is intravenous (IV).Ketamine may thus also be prepared in a formulation or pharmaceuticalcomposition appropriate for IV administration. Ketamine can be admixedwith a pharmaceutically acceptable carrier or excipient as describedabove. By way of example, ketamine can be formulated in a salinesolution for intravenous administration.

Intranasal Administration

A preferred mode of administration is intranasal administration, i.e.,through the nasal mucosa and through the nose-brain pathway directlyinto the cerebrospinal fluid. Ming Ming Wen, Discov Med, “OlfactoryTargeting Through Intranasal Delivery of Biopharmaceutical Drugs to theBrain—Current Development,” 2011, 11:497-503, is hereby incorporated byreference in its entirety. As discussed in Wen, drugs administeredintranasally may reach the brain via alternatives pathways. In onepathway, drugs, e.g., ketamine, are absorbed systemically, followingabsorption through the blood vessels of the nasal respiratoryepithelium. Drugs delivered via this systemic pathway must first crossthe blood brain barrier, prior to reaching the brain. In an alternativedelivery pathway, drugs administered intranasally can be rapidlytransported into the CNS via the connection between the olfactoryepithelium at the roof of the nasal cavity and the trigeminal system ofthe brain. This affords a direct connection, with no synapse between theolfactory neurons and the brain. The pathway thus allows transport ofactive agents to the brain without passage through the blood brainbarrier.

Excipients that may improve intranasal administration of ketamineinclude mucoadhesives (e.g., carbopol, carboxymethylcellulose, andhyaluronan), penetration enhancers that improve permeability andbioavailability of ketamine upon contact of the nasal mucosa (e.g.,peppermint oil, N-tridecyl-beta-D-maltoside, and hexarelin). Chitosan,for example, has both mucoadhesive and penetration enhancing properties.Other agents that can be used to in formulations for intranasal deliveryinclude liposomes (e.g., cationic liposomes and liposomes coated withpolyethylene glycol (PEG), vasoconstrictors (e.g., phenylephrine), tolimit absorption through the systemic pathway and increase absorptionthrough the olfactory epithelium. Additional formulations and methodsfor intranasal administration are found in Ilium, L., J Pharm Pharmacol,56:3-17, 2004 and Ilium, L., Eur J Pharm Sci 11:1-18, 2000, each ofwhich is hereby incorporated by reference in its entirety.

Either of liquid and powder intranasal formulations may be used.Ketamine, for example, may be combined with a dispersing agent, ordispersant, and administered intranasally in an aerosol formulationoptimized for intranasal administration.

Intranasal liquid aerosol formulations contain ketamine and a dispersingagent in a physiologically acceptable diluent. Aerosolized formulationsare broken down into liquid or solid particles in order to ensure thatthe aerosolized dose actually reaches the mucous membranes of the nasalpassages. The term “aerosol particle” is used to describe the liquid orsolid particle suitable for intranasal administration, i.e., that willreach the mucous membranes. Other considerations, such as constructionof the delivery device, additional components in the formulation, andparticle characteristics are important. These aspects of intranasaladministration of a drug are well known in the art, and manipulation offormulations, aerosolization means and construction of a delivery devicerequire at most routine experimentation by one of ordinary skill in theart.

Intranasal aerosol formulations can also be prepared as a dry powderformulation comprising a finely divided powder form of ketamine and adispersant. For example, the dry powder formulation can comprise afinely divided dry powder containing ketamine, a dispersing agent andalso a bulking agent. Bulking agents useful in conjunction with thepresent formulation include such agents as lactose, sorbitol, sucrose,or mannitol, in amounts that facilitate the dispersal of the powder fromthe device.

Nasal formulations may be administered with the aid of a deliverydevice, e.g., an aerosol delivery. Any form of aerosolization known inthe art, including but not limited to spray bottles, nebulization,atomization or pump aerosolization of a liquid formulation, andaerosolization of a dry powder formulation, can be used.

Nasal formulations may be administered, for example, using a plasticsqueeze bottle with an aperture or opening dimensioned to aerosolize anaerosol formulation by forming a spray when squeezed. The opening isusually found in the top of the bottle, and the top is generally taperedto partially fit in the nasal passages for efficient administration ofthe aerosol formulation.

A useful device for intranasal administration is a small, hard bottle towhich a metered dose sprayer is attached. In one embodiment, the metereddose is delivered by drawing the ketamine solution into a chamber ofdefined volume, which chamber has an aperture dimensioned to aerosolizeand aerosol formulation by forming a spray when a liquid in the chamberis compressed. The chamber is compressed to administer the ketamine. Ina specific embodiment, the chamber is a piston arrangement. Such devicesare commercially available.

A preferred device for intranasal delivery of compositions andformulations is the OptiNose apparatus, which is commercially availablefrom OptiNose US Inc. (Yardley, Pa.).

Other devices useful for administering a dose intranasally are mucosalautomation device that provide atomization of topical solution acrossthe nasal and oropharyngeal mucous membranes that produce a typicalparticle size of 30 microns. An example of such a device is the LMA MADNasal™ device (LMA Company, San Diego, Calif.), which produces a typicalparticle size of 30 microns, has a system dead space of 0.09 mL, a tipdiameter of about 3/16″ (4 mm), and an applicator length of about 1¾″(44 mm) can be used.

In another embodiment, intranasal drug delivery is achieved by taking asolubilized medication (liquid form) and dripping it into the nose a fewdrops at a time, allowing it to run down onto the nasal mucosa. This canbe done using, e.g., a syringe.

In certain embodiments, the present disclosure provides liquid or powderaerosol formulations and dosage forms for intranasal administration(e.g., for use in treating subjects suffering from PTSD). In generalsuch dosage forms contain ketamine in a pharmaceutically acceptablediluent. Pharmaceutically acceptable diluents in such liquid aerosolformulations include but are not limited to sterile water, saline,buffered saline, dextrose solution, and the like. In a specificembodiment, a diluent that may be used in the present disclosure and/orin a pharmaceutical formulation of the present disclosure is phosphatebuffered saline or a buffered saline solution generally between the pH7.0-8.0 range, or water. The present disclosure contemplates the use ofany suitable diluent known in the art for intranasal administration.

Formulations may also include other agents, ingredients, and/orcomponents, e.g., that are useful for pH maintenance, solutionstabilization, or for the regulation of osmotic pressure, including, butnot limited to salts, such as sodium chloride, or potassium chloride,and carbohydrates, such as glucose, galactose or mannose, and the like.

Formulations for intranasal administration may include a “mucosalpenetration enhancer,” i.e., a reagent that increases the rate orfacility of transmucosal penetration of ketamine, such as but notlimited to, a bile salt, fatty acid, surfactant or alcohol. Examples ofpenetration enhancers include sodium cholate, sodium dodecyl sulphate,sodium deoxycholate, taurodeoxycholate, sodium glycocholate,dimethylsulfoxide or ethanol.

Formulations disclosed herein, e.g., intranasal formulations, mayinclude a dispersant. Preferably, a dispersant is pharmaceuticallyacceptable. Suitable dispersing agents are well known in the art, andinclude but are not limited to surfactants and the like. Suchsurfactants are generally used reduce surface induce aggregation causedby atomization of the solution forming a liquid aerosol. Examples ofsuch surfactants include, but are not limited to, polyoxyethylene fattyacid esters and alcohols, and polyoxyethylene sorbitan fatty acidesters. Amounts of surfactants used will vary, being generally withinthe range or 0.001 and 4% by weight of the formulation. Suitablesurfactants are well known in the art, and can be selected on the basisof desired properties, depending on the specific formulation.

Oral Administration

Contemplated for use herein are oral solid dosage forms, which aredescribed generally in Remington's Pharmaceutical Sciences, 18th Ed.1990 (Mack Publishing Co. Easton Pa. 18042) at Chapter 89). Solid dosageforms include tablets, capsules, pills, troches or lozenges, cachets,pellets, powders, or granules. An exemplary lozenge formulation isdescribed in Chong et al. Clin Drug Investig. 2009; 29(5):317-24. Also,liposomal or proteinoid encapsulation may be used to formulate thepresent compositions (as, for example, proteinoid microspheres reportedin U.S. Pat. No. 4,925,673). Liposomal encapsulation may be used and theliposomes may be derivatized with various polymers (e.g., U.S. Pat. No.5,013,556). A description of possible solid dosage forms for thetherapeutic is given by Marshall, K. In: Modern Pharmaceutics Edited byG. S. Banker and C. T. Rhodes Chapter 10, 1979. In general, theformulation includes the therapeutic agent and inert ingredients whichallow for protection against the stomach environment, and release of thebiologically active material in the intestine.

Also contemplated for use herein are liquid dosage forms for oraladministration, including pharmaceutically acceptable emulsions,solutions, suspensions, and syrups, which may contain other componentsincluding inert diluents; adjuvants, wetting agents, emulsifying andsuspending agents; and sweetening, flavoring, coloring, and perfumingagents.

For oral formulations, the location of release may be the stomach, thesmall intestine (the duodenum, the jejunem, or the ileum), or the largeintestine. One skilled in the art has available formulations which willnot dissolve in the stomach, yet will release the material in theduodenum or elsewhere in the intestine, e.g., by the use of an entericcoating. Examples of the more common inert ingredients that are used asenteric coatings are cellulose acetate trimellitate (CAT),hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55,polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, celluloseacetate phthalate (CAP), Eudragit L, Eudragit S, and Shellac. Thesecoatings may be used as mixed films.

A coating or mixture of coatings can also be used on tablets, which arenot intended for protection against the stomach. This can include sugarcoatings, or coatings which make the tablet easier to swallow. Capsulesmay consist of a hard shell (such as gelatin) for delivery of drytherapeutic (i.e. powder), for liquid forms a soft gelatin shell may beused. The shell material of cachets could be thick starch or otheredible paper. For pills, lozenges, molded tablets or tablet triturates,moist massing techniques can be used. The formulation of the materialfor capsule administration could also be as a powder, lightly compressedplugs, or even as tablets. These therapeutics could be prepared bycompression.

One may dilute or increase the volume of the therapeutic agent with aninert material. These diluents could include carbohydrates, especiallymannitol, lactose, anhydrous lactose, cellulose, sucrose, modifieddextrans and starch. Certain inorganic salts may be also be used asfillers including calcium triphosphate, magnesium carbonate and sodiumchloride. Some commercially available diluents are Fast-Flo, Emdex,STA-Rx 1500, Emcompress and Avicell.

Disintegrants may be included in the formulation of the therapeuticagent into a solid dosage form. Materials used as disintegrants includebut are not limited to starch, including the commercial disintegrantbased on starch, Explotab, Sodium starch glycolate, Amberlite, sodiumcarboxymethylcellulose, ultramylopectin, sodium alginate, gelatin,orange peel, acid carboxymethyl cellulose, natural sponge and bentonitemay all be used. The disintegrants may also be insoluble cationicexchange resins. Powdered gums may be used as disintegrants and asbinders, and can include powdered gums such as agar, Karaya ortragacanth. Alginic acid and its sodium salt are also useful asdisintegrants. Binders may be used to hold the therapeutic agenttogether to form a hard tablet and include materials from naturalproducts such as acacia, tragacanth, starch and gelatin. Others includemethyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose(CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose(HPMC) could both be used in alcoholic solutions to granulate thepeptide (or derivative).

An antifrictional agent may be included in the formulation to preventsticking during the formulation process. Lubricants may be used as alayer between the peptide (or derivative) and the die wall, and thesecan include but are not limited to; stearic acid including its magnesiumand calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin,vegetable oils and waxes. Soluble lubricants may also be used such assodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol ofvarious molecular weights, Carbowax 4000 and 6000.

Glidants that might improve the flow properties drug during formulationand to aid rearrangement during compression might be added. The glidantsmay include starch, talc, pyrogenic silica and hydrated silicoaluminate.

To aid dissolution of the therapeutic agent into the aqueous environmenta surfactant might be added as a wetting agent. Surfactants may includeanionic detergents such as sodium lauryl sulfate, dioctyl sodiumsulfosuccinate and dioctyl sodium sulfonate. Cationic detergents mightbe used and could include benzalkonium chloride or benzethomiumchloride. The list of potential nonionic detergents that could beincluded in the formulation as surfactants are lauromacrogol 400,polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fattyacid ester, methyl cellulose and carboxymethyl cellulose. Thesesurfactants could be present in the formulation of the protein orderivative either alone or as a mixture in different ratios.

Controlled release oral formulations may used in practicing the presentinvention. The therapeutic agent could be incorporated into an inertmatrix which permits release by either diffusion or leaching mechanisms,e.g., gums. Slowly degenerating matrices may also be incorporated intothe formulation. Some enteric coatings also have a delayed releaseeffect. Another form of a controlled release is by a method based on theOros therapeutic system (Alza Corp.), i.e., the therapeutic agent isenclosed in a semipermeable membrane which allows water to enter andpush agent out through a single small opening due to osmotic effects.

Other coatings may be used for the formulation. These include a varietyof sugars which could be applied in a coating pan. The therapeutic agentcould also be given in a film coated tablet and the materials used inthis instance are divided into 2 groups. The first are the nonentericmaterials and include methyl cellulose, ethyl cellulose, hydroxyethylcellulose, methylhydroxy-ethyl cellulose, hydroxypropyl cellulose,hydroxypropyl-methyl cellulose, sodium carboxy-methyl cellulose,providone and the polyethylene glycols. The second group consists of theenteric materials that are commonly esters of phthalic acid. A mix ofmaterials might be used to provide the optimum film coating. Filmcoating may be carried out in a pan coater or in a fluidized bed or bycompression coating.

Transdermal Administration

In another alternative embodiment, administration comprises transdermaladministration. Such treatment may be administered alone or may besupplemented with other antidepressant therapies as described herein.Transdermal administration includes passive or active transdermal ortranscutaneous modalities, including, for example, patches andiontophoresis devices, as well as topical application of pastes, salves,or ointments.

Those of skill in the art are well aware of general technologies fortransdermal drug delivery or administration of a therapeutic agent tothe skin. Transdermal drug delivery offers controlled release of a drugto the patient and transdermal patches are user-friendly, convenient,painless, and offer multi-day dosing which usually results in improvedpatient compliance. The methods of the invention for treating PTSDpatients with a transdermal administration of ketamine can includeadministering ketamine to skin of the face, head or body. Such aketamine composition can be administered to the skin of the face, scalp,temporal region, arms, stomach, thighs, back, neck and the like.Suitable skin of the face includes skin of the chin, the upper lip, thelower lip, the forehead, the nose, the cheek, the skin around the eyes,the upper eyelid, the lower eyelid or combinations thereof. Suitableskin of the scalp includes the front of the scalp, the scalp over thetemporal region, the lateral part of the scalp, or combinations thereof.Suitable skin of the temporal region includes the temple and the scalpover the temporal region and combinations thereof. The ketamine may beformulated into a bioadhesive patch or a bioadhesive strip with anocclusive covering. Alternatively, the transdermal ketamine compositionfor administration to the skin can be applied as a topical ointment, atopical gel, a lotion, a cream, a solution, a spray, a paint, a film, afoil, a cosmetic, to be applied to the skin in a layer with or withoutan occlusive dressing.

Intradermal administration of ketamine-containing compositions also iscontemplated. Intradermal administration of a therapeutic agent isdefined as within or between the layers of skin. In contrast,subcutaneous administration is defined as beneath the initial layer ofskin and intravenous is a systemic administration into the bloodstream.Administration of therapeutic agents by intradermal, intravenous orsubcutaneous injection is a common means of drug delivery and readilyperformed by one skilled in the art.

The compositions and formulation described herein may be administered bya health professional or by a patient. Patient self-administration ofketamine to treat PTSD is expressly contemplated. Intranasaladministration and administration via transdermal patch are particularlysuited to patient self-administration.

Additional Active Ingredients

Formulations for use in the methods described herein can include othertherapeutically or pharmacologically active ingredients in addition toketamine, such as but not limited to agents used for antidepressanttherapy. Such agents include, but are not limited to, antidepressants:e.g., biogenic amine non-selective reuptake inhibitors, e.g., tricyclicantidepressants like imipramine; serotonin selective reuptake inhibitorslike fluoxetine (Prozac); monoamine oxidase inhibitors (MAO-I) likephenelezine; other types of antidepressant medications includingatypical antidepressants. Antidepressants augmentation with othermedications e.g., lithium, T3, T4, etc. Other treatment modalities withantidepressant effects: electro-convulsive treatment (ECT); lighttherapy, psychotherapy e.g., cognitive or interpersonal therapy forPTSD.

In addition, administration of drugs, reported to ameliorate orexacerbate the symptoms of a neuropsychiatric disorder, include but arenot limited to compounds include antidepressants such as lithium salts,carbamazepine, valproic acid, lysergic acid diethylamide (LSD),p-chlorophenylalanine, p-propyidopacetamide dithiocarbamate derivativese.g., FLA 63; anti-anxiety drugs, e.g., diazepam; monoamine oxidase(MAO) inhibitors, e.g., iproniazid, clorgyline, phenelzine,tranylcypromine, and isocarboxazid; biogenic amine uptake blockers,e.g., tricyclic antidepressants such as desipramine, imipramine andamitriptyline; atypical antidepressants such as mirtazapine, nefazodone,bupropion; serotonin reuptake inhibitors e.g., fluoxetine, venlafaxine,and duloxetine; antipsychotic drugs such as phenothiazine derivatives(e.g., chlorpromazine (thorazine) and trifluopromazine)), butyrophenones(e.g., haloperidol (Haldol)), thioxanthene derivatives (e.g.,chlorprothixene), S and dibenzodiazepines (e.g., clozapine);benzodiazepines; dopaminergic agonists and antagonists e.g., L-DOPA,cocaine, amphetamine, a-methyl-tyrosine, reserpine, tetrabenazine,benztropine, pargyline; noradrenergic agonists and antagonists e.g.,clonidine, phenoxybenzamine, phentolamine, tropolone.

In another embodiment of the treatment methods, the compositionsadministered comprise compounds, in particular drugs, reported toameliorate or exacerbate the symptoms of oxidative stress disorder. Suchcompounds include reduced IS glutathione (GSH), glutathione precursors,e.g., N-acetylcysteine; antioxidants, e.g., vitamins E and C, betacarotene and quinones; inhibitors of lipid membrane peroxidation, e.g.,21-aminosteroid U74006F (tirilazad mesylate), and lazaroids;antioxidants such as mazindol; 2c dizocilpine maleate; selegiline;sulfhydryls N-acetyleysteine and cysteamine; dimethylthiourea; EUK-8 asynthetic, low molecular salen-manganese complex; syntheticmanganese-based metalloprotein superoxide dismutase mimic, SC52608; freeradical scavengers or suppressors, e.g., pegorgotein, tocotrienol,tocopheral, MDL 74,18, LY231617, MCI-186, AVS (nicaraven), allopurinol,rifampicin, oxypurinol, hypochlorous acid or recombinant human Cu,Zn-SOD.

Dosages

Effective amounts of ketamine in compositions including pharmaceuticalformulations, include doses that partially or completely achieve thedesired therapeutic, prophylactic, and/or biological effect. In aspecific embodiment, an effective amount of ketamine administered to asubject with PTSD is effective for treating one or more signs orsymptoms of PTSD. The actual amount effective for a particularapplication depends on the condition being treated and the route ofadministration.

In certain aspect, the present disclosure provides for administration ofa therapeutically effective dose of ketamine, i.e., a dose effective totreat PTSD. Specific dosages may be adjusted depending on conditions ofdisease, i.e., the severity of PTSD, the age, body weight, generalhealth conditions, sex, and diet of the subject, dose intervals,administration routes, excretion rate, and combinations of drugs. Any ofthe dosage forms described herein containing effective amounts ofketamine, either alone or in combination with one or more active agents,are well within the bounds of routine experimentation and therefore,well within the scope of the instant invention.

An initial dose may be larger, followed by smaller maintenance doses.The dose may be administered as infrequently as weekly or biweekly, orfractionated into smaller doses and administered daily, several timesdaily, semi-weekly, bi-weekly, quarterly, etc., to maintain an effectivedosage level. Preliminary doses can be determined according to animaltests, and the scaling of dosages for human administration can beperformed according to art-accepted practices. In certain embodiments, asubject may be administered 1 dose, 2 doses, 3 doses, 4 doses, 5 doses,6 doses or more of a ketamine-containing composition described herein.However, other ranges are possible, depending on the subject's responseto the treatment. Moreover, an initial dose may be the same as, or loweror higher than subsequently administered doses of ketamine.

The number and frequency of doses may be determined based on thesubject's response to administration of the composition, e.g., if one ormore of the patient's symptoms improve and/or if the subject toleratesadministration of the composition without adverse reaction; in somesubjects, a single dose is sufficient, other subjects may receive adaily, several times a day, every other day, several times per week,weekly, biweekly, semi-weekly, or monthly administration of acomposition containing ketamine as described herein. The duration andfrequency of treatment will depend upon the subject's response totreatment, i.e., if the subject's condition and/or one more symptoms ofPTSD improves.

In one example of a dosing regimen, an initial dose of ketamine is usedto treat PTSD, followed by titration of to a lower dose of ketamine tomaintain treatment of the PTSD. Such a regimen may be particularlyuseful, for example, to use a high dose of ketamine to treat acutesymptoms of PTSD, followed by titrating to a lower dose of ketamine, totreat chronic symptoms of PTSD.

In some aspects, a dose of ketamine to treat PTSD is approximately 0.001to approximately 2 mg/kg body, 0.01 to approximately 1 mg/kg of bodyweight, or approximately 0.05 to approximately 0.7 mg/kg of body weight.A subject (e.g., patient) suffering from PTSD may be administered(including self administration) a dose of ketamine of, for example,about 0.01 mg per kg of body weight (mg/kg), about 0.05 mg/kg, 0.1mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, or about 3mg/kg.

In another embodiment, the total dose of ketamine per nasaladministration ranges from about 1 to about 250 mg. By way ofnon-limiting example, ketamine doses of 1 mg, 2 mg, 4 mg, 5 mg, 10 mg,15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg,130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg,220 mg, 230 mg, 240 mg, and 250 mg are specifically contemplated.

In a certain embodiments, an intranasal or intravenous dose of ketaminefor a subject of 80 kg body weight is equal to or greater than about 40mg, for example, about 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg,80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240mg, or 250 mg.

In certain embodiments, intranasal administration of 8-32 mg ofketamine, corresponding to 0.13 to 0.53 mg/kg of body weight iscontemplated.

In some aspects, a dose of esketamine to treat PTSD is approximately0.001 to approximately 2 mg/kg body, 0.01 to approximately 1 mg/kg ofbody weight, or approximately 0.05 to approximately 0.7 mg/kg of bodyweight. A subject (e.g., patient) suffering from PTSD may beadministered (including self administration) a dose of esketamine of,for example, about 0.01 mg per kg of body weight (mg/kg), about 0.05mg/kg, 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg,about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg,about 0.9 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg,about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg,about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, orabout 3 mg/kg.

In another embodiment, the total dose of esketamine per intranasaladministration ranges from about 1 to about 250 mg. By way ofnon-limiting example, esketamine doses of 1 mg, 2 mg, 4 mg, 5 mg, 10 mg,15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg,130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg,220 mg, 230 mg, 240 mg, and 250 mg are specifically contemplated.

In another embodiment, the total dose of ketamine per intranasaladministration ranges from about 10 mg to about 300 mg, about 10 mg toabout 250 mg, about 10 to about 200 mg, about 15 to about 175 mg, about20 to about 175 mg, about 25 to about 150 mg, about 25 to about 125 mg,about 25 to about 100 mg, about 50 to about 100 mg, about 50 mg to about75 mg, about 75 mg to about 100 mg, or about 75 mg to about 200 mg.

In another embodiment, the total dose of esketamine per intranasaladministration ranges from about 10 mg to about 300 mg, about 10 mg toabout 250 mg, about 10 to about 200 mg, about 15 to about 175 mg, about20 to about 175 mg, about 25 to about 150 mg, about 25 to about 125 mg,about 25 to about 100 mg, about 50 to about 100 mg, about 50 mg to about75 mg, about 75 mg to about 100 mg, or about 75 mg to about 200 mg.

In a certain embodiments, an intranasal or intravenous dose ofesketamine for a subject of about 70-80 kg body weight is equal to orgreater than about 40 mg, for example, about 45 mg, 50 mg, 55 mg, 60 mg,65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg,130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg,220 mg, 230 mg, 240 mg, or 250 mg.

In certain embodiments, intranasal administration of 8-32 mg ofesketamine, corresponding to 0.13 to 0.53 mg/kg of body weight iscontemplated. In another embodiment, intranasal administration of atotal dose of between about 50-75 mg of esketamine, corresponding tobetween about 0.83 to 1.25 mg/kg of body weight is contemplated. Inanother embodiment, intranasal administration of a total dose of betweenabout 50-75 mg of esketamine, corresponding to between about 0.74 to 1.1mg/kg of body weight is contemplated.

In certain embodiments, intranasal administration of 8-32 mg ofketamine, corresponding to 0.13 to 0.53 mg/kg of body weight iscontemplated. In another embodiment, intranasal administration of atotal dose of between about 50-75 mg of ketamine, corresponding tobetween about 0.83 to 1.25 mg/kg of body weight is contemplated. Inanother embodiment, intranasal administration of a total dose of betweenabout 50-75 mg of ketamine, corresponding to between about 0.74 to 1.1mg/kg of body weight is contemplated.

Preferably, the effective dose of ketamine is titrated under thesupervision of a physician or medical care provider, so that the optimumdose for the particular application is accurately determined Thus, thepresent disclosure provides a dose suited to each individual subject(e.g., patient).

Once a dosage range is established, an advantage of compositions forintranasal administration of ketamine and methods of treatment viaintranasal administration is that the patient can administer (e.g.,self-administer) ketamine on an as-needed, dose-to-effect basis. Thus,the frequency of administration is under control of the subject. Yetanother particular advantage is that intranasal administration ofketamine is non-invasive, and facilitates ketamine's crossing of theblood-brain barrier.

The mild adverse effects of ketamine, e.g., dysphoria and/orhallucinations, sometimes called “ketamine dreams,” can occur uponadministration of a dose of greater than 50 mg of ketamine, and usuallyrequire doses greater than 100 mg of ketamine of total doseintranasally. When administering ketamine to treat PTSD, it ispreferable to administer a dose that is effective in treating PTSD, butis below the level that results in such side effects. It is possible,however, that higher doses of ketamine may be administered, particularlyin response to an acute episode of PTSD. Thus, co-administration of aketamine with the additional exemplary agents noted above may beindicated in order to achieve the beneficial anti-PTSD effects ofketamine without the side effects of this agent.

Methods of Treating Post-Traumatic Stress Disorder

Methods for treating a human patient with PTSD are directed to usingketamine to reduce or eliminate at least one symptom of PTSD in thepatient. Ketamine may be administered as a racemic mixture of(S)-ketamine and (R)-ketamine, or as enantiomerically enriched for aketamine enantiomer. A composition may be enriched to the extent that itis, for example, 90%, 95%, 99%, 99.9 or 99.99% of either of the(S)-ketamine and (R)-ketamine enantiomer.

In a specific embodiment, a method for treating a human patient withPTSD is directed to using esketamine to reduce or eliminate at least onesymptom of PTSD in the patient.

In certain embodiments, a composition comprising ketamine isadministered intranasally or intravenously to a patient suffering fromPTSD. In some embodiments, one or more secondary active agents, such asone of those described above, are coadministered to a patient in acombination therapy. As discussed above, “coadministered” does notnecessarily mean that the drugs and/or therapies are administered in acombined form (i.e., they may be administered separately (i.e., asseparate compositions or formulations) or together (the same formulationor composition) to the same or different sites at the same or differenttimes). In one embodiment, a patient suffering from PTSD is administereda combination therapy comprising ketamine and an anti-depressant agent(e.g., SSRI).

In other embodiments, the present disclosure also contemplates theprophylactic use of the ketamine-containing compositions andformulations disclosed herein. For example, in certain embodiments,presently provided are methods for inhibiting development ofpost-traumatic stress disorder (PTSD) in a human patient which comprisesintranasally or intravenously administering to a subject in need of suchinhibiting a composition comprising a therapeutically effective amountof ketamine for inhibiting the development of PTSD and/or one thedevelopment of one or more PTSD-like symptoms, wherein thetherapeutically effective amount is a dosage range of about dose ofbetween about 0.1 mg/kg per day to about 3.0 mg/kg/day. Thus, in certainembodiments, for example, a subject may be administered (includingself-administered) a composition or formulation comprising atherapeutically effective amount of ketamine prior to a situation inwhich the subject is likely to be exposed to traumatic stress, such asearly responders or military personnel, immediately after exposure totraumatic stress, and/or when the subject feels that his or her PTSDsymptoms are likely to appear.

In specific embodiments, the symptoms of PTSD are alleviated within 2hours of administration of the ketamine. As disclosed herein, symptomsof PTSD may be alleviated concomitant with administration of ketamine.

Treatment of PTSD may be achieved administration of a single dose of theketamine. Alternatively, multiple doses of ketamine may be administered.Administration of a single dose of ketamine can be sufficient toalleviate the effects of the PTSD for 7 days, 2 weeks and in some cases,longer.

IV administration of ketamine can be on an as needed basis, e.g., whensymptoms of PTSD appear. For IV administration, ketamine (e.g., doses ofat least 0.5 mg/kg) may be administered over a period of 40 minutes. IVadministration may be continued for up to 1 week, or longer. IVadministration of ketamine may also be effected at least twice, at leastthree times, at least four times, at least five time, at least sixtimes, at least seven times per week, and may be continued over a periodof two, three, four, five, six, seven, eight, nine or 10 weeks, or more.No serious adverse events caused by IV administration of ketamine havebeen observed. Any side effects observed are typically mild, e.g.,euphoria, elevated BP, increased libido, perceptual disturbances, andfurthermore these effects typically abate within 80 minutespost-infusion.

Administration of intranasal ketamine can be on an as needed basis,e.g., when symptoms of PTSD appear. In specific embodiments, theketamine is administered at least two, at least three, at least four, atleast five, at least six, at least seven, at least eight, at least ninetimes in fourteen days. In other embodiments, the ketamine isadministered at least two, at least three, at least four, at least five,at least six, at least seven, at least eight, at least nine times intwenty-one days. In other embodiments, the intranasal ketamine isadministered at least once a day, at least twice a day, at least threetimes per day, or more. In other embodiments, the intranasal ketamine isadministered at least once a week, at least twice a week, at least threetimes per week, or more frequently. In another embodiment, theintranasal ketamine is administered at least twice per months, or atleast once per months. Treatment can continue as long as needed.

Ketamine may also be used to treat PTSD in combination with a secondagent. When used in combination with ketamine, a second agent may beadministered as an adjunct therapy to ketamine, i.e., an individualsuffering from PTSD may be treated concurrently with ketamine and thesecond agent. Alternatively, an individual suffering from PTSD may betreated initially with ketamine, followed by cessation of ketaminetreatment and initiation of treatment with a second agent. Such atreatment may be warranted, for example, if a patient exhibits unwantedside effects or reduced response to ketamine treatment. Alternatively,in certain embodiments, ketamine is used as an initial treatment forPTSD, e.g., by administration of one, two or three doses, and a secondagent is administered to prolong the effect of ketamine on reducingPTSD, or alternatively, to boost the effect of ketamine reducing PTSD. Aperson of ordinary skill in the art will recognize that other variationsof the presented schemes are possible, e.g., initiating treatment of aPTSD patient with ketamine, followed by a period wherein the patient istreated with a second agent as adjunct therapy to ketamine treatment,followed by cessation of ketamine treatment.

Exemplary second agents for use with ketamine to treat PTSD areanxiolytics, antidepressants, including for example, SRIs, SSRI andlithium. Specific examples of second agents for use with ketamine intreating PTSD are paroxetine, sertraline, lithium, riluzole, prazosin,lamotrigine, and ifenprodil.

In certain embodiments, a second agent is used in combination withketamine to treat PTSD, or following an initial treatment phase of PTSDwith ketamine, wherein the second agent boosts the positive effect orketamine in treatment of PTSD or sustains the positive effect ofketamine in treatment of PTSD.

In alternative embodiments, intravenous, oral, and transdermaladministration of ketamine are contemplated. In one alternativeembodiment, the invention thus provides a method of treating a humanpatient for PTSD, comprising intravenously administering a compositioncomprising ketamine to the patient at a dosage sufficient to reduce oreliminate the symptoms of the PTSD. In another alternative embodiment,the invention thus provides a method of treating a human patient forPTSD, comprising transdermally administering a composition comprisingketamine to the patient at a dosage sufficient to reduce or eliminatethe symptoms of the PTSD. In another alternative embodiment, theinvention thus provides a method of treating a human patient for PTSD,comprising orally (e.g., liquid or solid (e.g., lozenge) dosage form)administering a composition comprising ketamine to the patient at adosage sufficient to reduce or eliminate the symptoms of the PTSD. Inmore specific embodiments, the ketamine is in a pharmaceuticallyacceptable carrier and is administered at a dose of between about 0.1mg/kg per day to about 3.0 mg/kg/day.

The methods of the invention may be achieved through a method thatcomprises intravenous, oral, or transdermal administration of multipledoses of the ketamine. Administration intravenous, oral, or transdermaladministration ketamine can be on an as needed basis, e.g., whensymptoms of PTSD appear. In specific embodiments, the ketamine isadministered at least two, at least three, at least four, at least five,at least six, at least seven, at least eight, at least nine times infourteen days. In other embodiments, the ketamine is administered atleast two, at least three, at least four, at least five, at least six,at least seven, at least eight, at least nine times in twenty-one days.In other embodiments, the ketamine is administered at least once a day,at least twice a day, at least three times per day, or more. In otherembodiments, the ketamine is administered at least once a week, at leasttwice a week, at least three times per week, or more frequently. Inanother embodiment, the ketamine is administered at least twice permonths, or at least once per months. Treatment can continue as long asneeded.

Typically, a subject suffering from PTSD was exposed to a traumaticevent in which the person experienced, witnessed, or was confronted withan event or events that involved actual or threatened death or seriousinjury, or a threat to the physical integrity of self or others and theperson's response involved intense fear, helplessness, or horror.Typically, the traumatic event is persistently re-experienced in one ormore of the following ways: recurrent and intrusive distressingrecollections of the event, including images, thoughts, or perceptions,recurrent distressing dreams of the event, acting or feeling as if thetraumatic event were recurring (includes a sense of reliving theexperience, illusions, hallucinations, and dissociative flashbackepisodes, including those that occur on awakening or when intoxicated),intense psychological distress at exposure to internal or external cuesthat symbolize or resemble an aspect of the traumatic event,physiological reactivity on exposure to internal or external cues thatsymbolize or resemble an aspect of the traumatic event. An individualsuffering from PTSD also has persistent avoidance of stimuli associatedwith the trauma and numbing of general responsiveness (not presentbefore the trauma), as indicated by 3 or more of the following: effortsto avoid thoughts, feelings, or conversations associated with thetrauma, efforts to avoid activities, places, or people that arouserecollections of the trauma, inability to recall an important aspect ofthe trauma, significantly diminished interest or participation insignificant activities, feeling of detachment or estrangement fromothers, restricted range of affect (e.g., unable to have lovingfeelings), sense of a foreshortened future (e.g., does not expect tohave a career, marriage, children, or a normal life span), persistentsymptoms of increased arousal (not present before the trauma), asindicated by 2 or more of the following: difficulty falling or stayingasleep, irritability or outbursts of anger, difficulty concentrating,hypervigilance, exaggerated startle response. The disturbance, which haslasted for at least a month, causes clinically significant distress orimpairment in social, occupational, or other important areas offunctioning. The symptoms expected to be decreased following treatmentwith ketamine include re-experiencing of the traumatic experience in theform of intrusive memories, nightmares, flashbacks, and emotional andphysical reactions triggered by reminders of the trauma; distancing fromothers, decreased interest in activities and other people, numbing offeelings, and avoidance of trauma reminders; and hyperarousal symptoms,including disrupted sleep, irritability, hypervigilance, decreasedconcentration, and increased startle reflex.

In certain embodiments, it can be determined whether a method fortreating PTSD, as disclosed herein, is effective, by determining whetherone or more symptoms of PTSD is reduced or eliminated. Psychiatricevaluations of a patient being treated with a therapy disclosed hereincan be conducted to determine whether the therapy (e.g., IV orintranasal administration of ketamine) is effective. In certainembodiments, the psychiatric evaluation may be carried out beforetreatment, at the time of treatment, during treatment, and/or aftertreatment. When the psychiatric evaluation is carried out both beforetreatment and after (and/or during) treatment with a therapy asdisclosed herein. The results of the evaluation before treatment canprovide a baseline for comparison to the results of the evaluationduring and/or after treatment. However, in some embodiments, psychiatricevaluation is conducted only after treatment.

The methods for using ketamine to treat PTSD described herein may alsobe used to treat co-morbid conditions that respond to ketamine. Majordepressive disorder, for example, exhibits co-morbidity with PTSD. Incertain embodiments, for example, the methods described herein can thusbe used to treat co-morbid PTSD and major depressive disorder.

By way of example, any one or more of the following psychiatricevaluations of a patient, which are well known in the art, can beconducted before and/or after administration of ketamine in order todetermine whether PTSD has been treated. Examples of psychiatricevaluation tools and questionnaires used to evaluate PTSD and PTSDsymptoms are as follows:

Measures

Both clinician-administered and validated self-report instruments areused, with the aim of measuring baseline symptomatology as well as drugactions on (1) the overall severity of the disorder, (2) the coresymptoms of PTSD, and (3) depressed mood. Below is a description of theinstruments used. Table 4 provides an overview.

The Diagnostic and Statistical Manual of Mental Disorders (DSM-5)includes the revised diagnostic criteria for PTSD. See, AmericanPsychiatric Association: Diagnostic and Statistical Manual of MentalDisorders, Fifth Edition. Arlington, Va., American PsychiatricAssociation, 2013. See alsoptsd.va.gov/professional/PTSD-overview/dsm5_criteria_ptsd.asp on theWorldWideWeb.

The Structured Clinical Interview for DSM-IV Axis I Disorders, PatientEdition (SCID-P) is a semi-structured interview that provides probequestions as well as follow-up questions to be asked by the clinician toassist in diagnosis. First et al., Structured Clinical Interview forDSM-IV TR Axis I Disorders, Research Version, Patient Edition(SCID-I/P). New York: New York State Psychiatric Institute, BiometricsResearch; 2001. It includes an overview to obtain information aboutdemographics, work, chief complaint, history of present illness, pasthistory, treatment history, and current functioning. The main body ofSCID-P includes 9 modules that are designed to diagnose 51 mentalillnesses in all.

The SCID-P for DSM-5 is the SCID—Patient version, and is the nextedition of the SCID modified to incorporate the new DSM-5 criteria.

The Clinician-Administered PTSD Scale (CAPS) is a structured clinicalinterview designed to assess the essential features of PTSD as definedby the DSM-IV. Weathers et al., Clinician-administered PTSD scale: areview of the first ten years of research. Depress Anxiety. 2001;13(3):132-156. The CAPS can be used to provide categorical ratings ofdiagnostic status as well as a quantitative index of symptom severity.Both frequency and intensity scores are derived for each individualsymptom. The CAPS total score is based on an individual's response tothe 17 items that assess the frequency and intensity of current PTSDsymptoms. Subscales of the CAPS are utilized to assess specific symptomclusters. Our research group has extensive experience using the CAPSfrom ongoing PTSD studies. The total score can range from 0 to 136.

The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a 30-itemstructured interview that can be used to make current (past month)diagnosis of PTSD, make lifetime diagnosis of PTSD, and to assess PTSDsymptoms over the past week. CAPS-5 is a 30-item questionnaire,corresponding to the DSM-5 diagnosis for PTSD. The language of theCAPS-5 reflects both changes to existing symptoms and the addition ofnew symptoms in DSM-5. CAPS-5 asks questions relevant to assessing thedissociative subtype of PTSD (depersonalization and derealization), butno longer includes other associated symptoms (e.g., gaps in awareness).As with previous versions of the CAPS, CAPS-5 symptom severity ratingsare based on symptom frequency and intensity (except for amnesia anddiminished interest which are based on amount and intensity). However,CAPS-5 items are rated with a single severity score in contrast toprevious versions of the CAPS which required separate frequency andintensity scores. See Weathers, F. W., et al (2013). TheClinician-Administered PTSD Scale for DSM-5 (CAPS-5). Interviewavailable from the National Center for PTSD at ptsd.va.gov on theWorldWideWeb.

The Treatment Outcome PTSD Scale (TOP-8) is a briefinterviewer-administered scale designed specifically for the assessmentof commonly occurring signs and symptoms of PTSD that are subject tochange in response to treatment (Davidson, J. R., & Colket, J. T.(1997). The eight-item treatment-outcome post-traumatic stress disorderscale: A brief measure to assess treatment outcome in post-traumaticstress disorder. International Clinical Psychopharmacology, 12(1),41-45). The TOP-8 is comprised of eight items, each measured on a scaleof 0-4, with defined anchors given for each item. The items arerepresentative of the three core features of PTSD with a maximumpossible score of 32.

The Hamilton Psychiatric Rating Scale for Anxiety (HAM-A) is a widelyused observational rating measure of anxiety severity. The scaleconsists of 14 items. Each item is rated on a scale of 0 to 4. Thisscale is administered to assess the severity of anxiety and itsimprovement during the course of treatment. The HAM-A total score is thesum of the 14 items and the score ranges from 0 to 56. Hamilton M. TheAssessment of Anxiety-States by Rating. Br J Med Psychol. 1959;32(1):50-55.

The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-iteminstrument used for the evaluation of depressive symptoms in adults andfor the assessment of any changes to those symptoms. Montgomery S. A.,et al., A new depression scale designed to be sensitive to change. Br JPsychiatry. 1979 April; 134:382-389. Each of the 10 items is rated on ascale of 0 to 6, with differing descriptors for each item. Theseindividual item scores are added together to form a total score, whichcan range between 0 and 60 points. The estimated time to administer thisscale is 20 minutes. Inter-rater reliability of the scale is high andscores correlate significantly with those of the HAM-D. On the infusiondays a modified MADRS is used that excludes the sleep and appetiteitems.

The Young Mania Rating Scale, item 1 (YMRS-1) used to assess moodelevation on the infusion days. Young R C, et al. Rating-Scale forMania—Reliability, Validity and Sensitivity. Br J Psychiatry. 1978;133(NOV):429-435.

The Brief Psychiatric Rating Scale (BPRS) is used to assess acutebehavioral changes during the infusions. Overall J E et al., The BriefPsychiatric Rating-Scale. Psychol Rep. 1962; 10(3):799-812 Four key BPRSitems for the positive (+) symptoms of psychosis are used: conceptualdisorganization, hallucinatory behavior, suspiciousness, and unusualthought content. Three items representing the negative (−) symptoms ofpsychosis will also be used: blunted affect, emotional withdrawal, andmotor retardation.

The Clinician-Administered Dissociative States Scale (CADSS) is used tomeasure dissociative effects during the infusions. Bremner J D, et al.,Measurement of Dissociative States with the Clinician-AdministeredDissociative States Scale (CADSS). J Trauma Stress. 1998; 11(1):125-136The scale includes 19 questions and 8 observer ratings scored from 0(not at all) to 4 (extremely). The CADSS measures impairment in bodyperception, environmental perception, time perception, memoryimpairment, and feelings of unreality.

The Patient Rating Inventory of Side Effects (PRISE) is a patientself-report used to qualify side effects by identifying and evaluatingthe tolerability of each symptom. Levine J, Schooler N R. SAFTEE: Atechnique for the systematic assessment of side effects in clinicaltrials. Psychopharmacol Bull. 1986; 22(2):343-381.

The Clinical Global Impression (CGI) scale assesses treatment responsein psychiatric patients. The administration time is 2 minutes. Thisscale consists of three items: Severity of Illness (item 1); GlobalImprovement (item 2); and Efficacy Index (item 3). Item 1 is rated on aseven-point scale (1=normal, 7=among the most extremely ill patients) asis item 2 (1=very much improved, 7=very much worse). Each includes anadditional response of “not assessed.” Item 3 is rated on a four-pointscale (from “none” to “outweighs therapeutic effect”). Only items 1(CGI-Severity or CGI-S) and 2 (CGI-Improvement or CGI-I) are used.

The Impact of Events Scale (IES) is one of the most widely usedself-report measures of stress reactions to traumatic events. HorowitzM, Wilner N, Alvarez W. Impact of Event Scale: a measure of subjectivestress. Psychosom Med. 1979 May; 41(3):209-218. See also, Weiss D S,Marmar C R. The Impact of Event Scale—Revised In: Wilson J, Keane T M,eds. Assessing psychological trauma and PTSD. New York: Guilford;1996:399-411. It measures both intrusion and avoidance. A 2002 reviewthat evaluated its psychometric properties revealed high internalconsistencies for both subscales (intrusion: mean α=0.86; avoidance:mean α=0.82), adequate test-retest reliability for intervals of >1 year,and good internal and external validity. Sundin E C, Horowitz M J.Impact of Event Scale: psychometric properties. Br J Psychiatry. 2002March; 180:205-209. Correlations between IES subscales and PTSDdiagnosis assessed with the CAPS are high (>0.75). Id. The IES isconsidered particularly useful as a measure of the intrusive andavoidant processes that mediate between the experience of trauma andsubsequent adjustment. Joseph S. Psychometric evaluation of Horowitz'sImpact of Event Scale: a review. J Trauma Stress. 2000 January;13(1):101-113. The total score can range from 0 to 75.

The Posttraumatic Stress Disorder Checklist (PCL-5) is a 17-itemself-report measure reflecting DSM-5 symptoms of PTSD. The PCL-5measures symptoms in response to stressful situations (Weathers, F., etal. (1993). The PTSD checklist (PCL): Reliability, validity, anddiagnostic utility. Annual Convention of the International Society forTraumatic Stress Studies, San Antonio, Tex.).

The Quick Inventory of Depressive Symptomatology, Self Report (QIDS-SR)is a 16-item self rated instrument designed to assess the severity ofdepressive symptoms present in the past seven days. Rush A J, Trivedi MH, Ibrahim H M et al. The 16-Item quick inventory of depressivesymptomatology (QIDS), clinician rating (QIDS-C), and self-report(QIDS-SR): a psychometric evaluation in patients with chronic majordepression. Biol Psychiatry. 2003; 54(5):573-583. The 16 items cover thenine symptom domains of major depression, and are rated on a scale of0-3. Total score ranges from 0 to 27, with ranges of 0-5 (normal), 6-10(mild), 11-15 (moderate), 16-20 (moderate to severe), and 21+ (severe).

The Childhood Trauma Questionnaire (CTQ) is a 28-item self-reportinstrument that assesses childhood trauma in the following areas:physical, sexual and emotional abuse and physical and emotional neglect.Bernstein D P, Stein J A, Newcomb M D et al. Development and validationof a brief screening version of the Childhood Trauma Questionnaire.Child Abuse Negl. 2003 February; 27(2):169-190. Each item is rated on ascale of 1 (never true) to 5 (very often true). The 5 subscales are thentotaled, with scores ranging from 5-25 for each traumatic category.

Visual Analogue Scales (VAS) are used to assess subjective statechanges. Bond A, Lader M. The use of analogue scales in ratingsubjective feelings. Br J Med Psychol. 1974; 47(3):211-218. They are100-mm horizontal lines marked proportionately to the perceivedintensity of the subjective experience (0=not at all, to 10=extremely)for the following states: anxious, depressed, drowsy, high, hungry, andnauseous.

The Sheehan Disability Scale (SDS) is the most frequently usedself-report disability measure. It has demonstrated sensitivity toimpairment and changes as a result of treatment across a wide range ofpsychiatric disorders. The SDS asks only about current levels ofimpairment, providing no indication of whether the person has donebetter or worse in the past, thus making it a reasonable short-termoutcome measure that is un-confounded by historical impressions. Thedependent variable is the total score, which is based on the sum ofthree 10-point items (work, social life, and family life), with higherscores reflecting greater disability. Sheehan D. The Anxiety Disease.New York, N.Y.: Scribner; 1983.

The Connor-Davidson Resilience Scale (CD-RISC) is a 25-item self-reportscale, each rated on a 5-point scale (0-4), with higher scoresreflecting greater resilience (Connor K M & Davidson, J R T. Developmentof a new resilience scale: the Connor-Davidson Resilience Scale(CD-RISC). Depression and Anxiety, 2003: 18: 71-82).

The Wechsler Abbreviated Scale of Intelligence 2-Subtest (WASI-2) is areliable brief measure of IQ for 6 to 89 year-olds that takes 15 minutesto complete and includes Vocabulary (an estimate of verbal fluidabilities) and Matrix Reasoning (an estimate of nonverbal fluidabilities). Wechsler D. Wechsler Abbreviated Scale of Intelligence SanAntonio, Tex.: Psychological Corporation; 1999. It is extensively usedin clinical, educational, and research settings. Average reliabilitycoefficient is 0.96 and test-retest reliability is 0.88.

The Hopkins Verbal Learning Test (HVLT) is a repeatable test of memoryacquisition and delayed recall of words. Subjects are presented with thesame 12-item list for 3 learning trials and asked each time to repeatthe items on each list. Delayed recall and recognition conditions areadministered later. Dependent variables used in this study include totallearning over the 3 trials (for the acquisition variable) and totaldelayed recall score (for the recall component). Brandt J, Benedict R.Hopkins Verbal Learning Test, Revised. Odessa, Fla.: PsychologicalAssessment Resources; 1997.

The Profile of Mood States-Bipolar (POMS-Bi) scale measures moods andfeelings primarily in clinical rather than nonclinical settings. It canhelp to determine an individual's psychiatric status for therapy, or beused to compare mood profiles associated with various personalitydisorders. It is also a useful instrument in identifying the effects ofdrug treatments.

The Post-Traumatic Cognitions Inventory (PTCI) is a 33-item scale, whichis rated on a Likert-type scale ranging from 1 (totally disagree) to 7(totally agree). Scale scores are formed for the three subscales, whichshow a high degree of intercorrelation (rs=0.57-0.75).

The New Cognitions scale is a 6-item pilot scale, which is rated on aLikert-type scale ranging from 1 (not at all) to 4 (a lot). The scale isbased on the Post Traumatic Growth Inventory (PTGI) from which itemshave been directly selected (new items were added to the scale as well),and on the Brief-COPE (see Carver, C. S. (1997) “You want to measurecoping but your protocol's too long: Consider the brief COPE.”International Journal of Behavioral Medicine 4; 92-100).

The Medical Outcomes Study (MOS) Social Support Survey is a 19-itemself-report measure designed to assess levels of functional socialsupport. The MOS-SS has two subscales (emotional and instrumental socialsupport) to identify potential social support deficits (Sherbourne, C.D. & Stewart, A. L. (1991). “The MOS Social Support Survey.” Soc Sci Med32(6): 705-714).

The Purpose in Life test-Short Form (PIL-SF) is a brief, 4-item form ofthe 20-item Purpose in Life test. This scale asks respondents to reportto what extent they have achieved their goals in life, and to whatextent they perceive their life to be meaningful or purposeful.(Schulenberg et al 2010; Psychotherapy (Chic). 2008 December;45(4):447-63).

Posttraumatic Growth Inventory (PTGI)-Short Version is a 10-itemshortened version of the PTGI self-report questionnaire (ref). It asksrespondents to rate the extent to which they have changed as the resultof experiencing a highly stressful life event. Items span positivechanges in five domains: relating to others, new possibilities, personalstrength, spiritual change, and appreciation of life (Cann, A., et al.(2010). A short form of the Posttraumatic Growth Inventory. Anxiety,Stress & Coping, 23, 127-137).

The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)is a self-report scale measuring the degree of enjoyment andsatisfaction experienced by subjects in various areas of dailyfunctioning. The summary scores are reliable and valid measures of thesedimensions in a group of depressed subjects (Endicott J, et al. Qualityof Life Enjoyment and Satisfaction Questionnaire: A New Measure.Psychopharmacology Bulletin; 1993; 29:321-326).

In other embodiments, determining whether a therapy disclosed herein iseffective for treating PTSD can be based on the self-evaluation of thepatient being treated, e.g., if the patient reports that one or moresymptoms of his or her PTSD has been treated.

Typically, the effects of treatment with a composition or formulationdisclosed herein are observed by the patient and/or, e.g., the patient'sphysician, within a predetermined time frame from the time ofadministration. Typically, the predetermined time frame is startingwithin 2 hours of the administration and up to 24 hours of theadministration of the composition or formulation. In other embodiments,the predetermined time frame is within 0.5 hours, 1 hour, 2.5 hours, 3hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10hours, 10.5 hours, 11 hours, 11.5 hours, 12 hours, 18 hours, 24 hours,48 hours, or 72 hours following administration of the composition orformulation.

In yet other embodiments, the predetermined time frame is within 1 day,2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 14 days followingadministration of the composition or formulation.

In still other embodiments, the predetermined time frame is within 1minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, 25minutes, or 30 minutes following administration of the composition orformulation.

Predictive Value of Ketamine-Induced Memory Impairments on Outcome

Having repeated intrusive memories of the trauma exposure is one of thecore symptoms of PTSD. Patients with PTSD are known to displayimpairments in learning and memory during neuropsychological testing.These memory disturbances may be at least partially due to dysregulationin glutamatergic pathways. Further, experimental studies have shownmemory disruption during ketamine infusion, which is thought to resultfrom interference with the retrieval processes necessary for recall.This effect likely includes glutamatergic action on the hippocampus. Theacute effects of IV ketamine on memory in patients with PTSD block theirdistressing intrusive memories, or at least the emotional contentassociated with it. The extent of memory impairment induced by ketamine(measured using the Hopkins Verbal Learning Test or HVLT) on theinfusion days may be a positive predictor of outcome.

EXAMPLES

The present disclosure is described further below in working exampleswhich are intended to further describe the invention without limitingthe scope therein.

Example 1 Intravenous Ketamine Treatment of PTSD: Case Studies

In a ketamine infusion study in patients with treatment resistantdepression (TRD), ketamine (0.5 mg/kg IV) was administered open-labeland combined with pre-infusion treatment with a single oral dose oflamotrigine (300 mg) or placebo administered under double-blindconditions. Preliminary analyses were recently performed on a sample of16 patients. Ketamine reduced clinical depression scores, as measuredusing the percentage reduction in Montgomery-Asberg Depression RatingScale (MADRS) scores from baseline to 24 hours post-infusion.Self-reported mood also improved, as measured using the Quick Inventoryof Depressive Symptoms, Self-Report version (QIDS-SR). A strong positivecorrelation between individual childhood trauma (abuse and/or neglect)and the antidepressant response (MADRS: r=0.55, p=0.03; QIDS-SR: r=0.59,p=0.02).

The effect of ketamine on Hamilton Anxiety Rating Scale (HAM-A) scoreswas also measured. A strong positive correlation between the magnitudeof the ketamine-induced reduction in HAM-A scores and personal historyof childhood trauma measured using the Childhood Trauma Questionnaire(CTQ; n=15, r=0.59, p=0.02) was observed. In view of these results, apossible role of trauma in the therapeutic efficacy of ketamine wasfurther investigated. Two of the four TRD patients with the highest CTQthus far had a co-morbid current PTSD diagnosis. Patient A, sufferedfrom distressing intrusive memories, nightmares, flashbacks,hypervigilance, poor concentration, and depressed mood. Patient Adescribed her PTSD and MDD symptoms as chronic, but having intensifiedover time, due to ongoing events in her life. Patient A had a CTQ scoreof 81 at baseline. During ketamine infusion, when queried about feelingsof guilt and worthlessness, Patient A exhibited a striking, almostinstantaneous cognitive revision of adverse events in her life.

After observing the magnitude of the therapeutic effect of ketamine inPatient A, TRD patients with a co-morbid current PTSD diagnosis wereadministered the Clinician-Administered PTSD Scale (CAPS) and the Impactof Events Scale (IES) before and after ketamine infusion. Patient M hada CTQ score of 108, a CAPS score of 81 (out of 136) and an IES score of48 (out of 75). The day after ketamine infusion, Patient M reported thathe felt an “intellectual distance” from the emotional content of priortraumatic events that allowed him to feel more in control. Patient Mfurther described feeling relieved of a compulsion to continuouslyanalyze his past, identify ways in which he might have circumventedtrauma, and subsequently punish himself for his failure to avoid trauma.One week post-infusion, Patient M's CAPS score had dropped by 90% andcould be considered a remission (defined as CAPS <20). Two weekspost-infusion, Patient M maintained his “intellectual distance” from theemotional content associated with his trauma. Patient M's baseline andpost-infusion IES scores presented in Table 1.

TABLE 1 CAPS IES Baseline (pre-ketamine) 81 48 +40 min (post-ketamine)33 +240 min 3 +24 hours 16 +72 hours 5 +1 week 8 5 +2 weeks 27 15

Patients A and M were the two patients with the largest ketamine-inducedpercentage reductions in MADRS, QIDS-SR and HAM-A scores in the entiresample.

Example 2 Intravenous Ketamine Treatment of PTSD: Controlled Study

This Example demonstrates that IV administered ketamine inhibited thesymptoms of PTSD. In patients with co-morbid major depressive disorder,IV administration of ketamine inhibited symptoms of both PTSD and MDD.

Patients with chronic PTSD were enrolled in a controlled study. Eligibleparticipants were between 18 and 55 years of age, had a primarydiagnosis of PTSD assessed with the Structured Clinical Interview forDSM-IV-TR Axis I Disorders-Patient Version (SCID-UP) (First et al.,supra) and a score of at least 50 on the Clinician-Administered PTSDScale (CAPS) (Weathers et al., supra). Exclusion criteria includedlifetime history of psychotic or bipolar disorder, current bulimia oranorexia nervosa, alcohol abuse or dependence in the previous threemonths, serious unstable medical illness or sleep apnea, active suicidalor homicidal ideation on presentation, or current use of anypsychotropic medications. All patients underwent a physical examinationand laboratory screening including routine hematologic, biochemical andurine toxicology testing, as well as an electrocardiogram to rule outunstable medical illness and active substance use. To receive the secondIV infusion, a CAPS score of at least 50 was required prior to thesecond infusion. The Institutional Review Board at Mount Sinai approvedthe study, and informed consent was obtained from all studyparticipants.

Procedures

Study participants were free of concomitant psychotropic medications fortwo weeks prior to randomization and for the duration of the study. Foreach procedure day, patients were assigned to receive a single IVinfusion of ketamine hydrochloride (0.5 mg/kg) or midazolam (0.045mg/kg), administered over 40 minutes. Order of infusions(ketamine-midazolam or midazolam-ketamine) was randomly assigned andadministrations were two weeks apart. Midazolam was chosen as the activeplacebo control because its pharmacokinetic parameters and non-specificbehavioral effects are similar to those of ketamine. Only the researchpharmacy was aware of drug identity, and all study personnel, includinginvestigators, anesthesiologists, raters, patients and data analystswere blinded to randomization order.

Following admission and an overnight fast, an indwelling catheter wasplaced in the antecubital vein of the non-dominant arm. Pulse, bloodpressure, pulse-oximetry and ECG monitoring were instituted (seeMurrough J et al. Antidepressant efficacy of ketamine intreatment-resistant major depression: a two-site, randomized controlledtrial. The American Journal of Psychiatry. 2013 Oct. 1;170(10):1134-42). Ratings were administered by a trained rater duringthe infusion and at 240 minutes after the start of the infusion. Adifferent rater, blinded to the ratings during post-infusion oninfusion, administered ratings at pre-infusion baseline, 24 hours(Day 1) post-infusion (before patients were discharged from thehospital), 48 hours (Day 2), 72 hours (Day 3), and 7 days (Day 7)post-infusion. Ratings were also administered at 10 and 13 dayspost-infusion, though data analyses focused on the first weekpost-infusion due to the expected duration of ketamine action. Patientswere instructed to abstain from taking psychotropic medications and fromusing alcohol or substances of abuse for the duration of the trial. Asdescribed above, patients who scored ≧50 on the CAPS 2 weeks after thefirst infusion received an infusion of the second study drug. Patientswhose symptoms remained significantly improved at 2 weeks post-infusion,indicated by a score <50 at 2 weeks, were considered to have completedthe study after one infusion.

Outcomes

The primary outcome was PTSD symptom severity at 24 hours post-infusion,assessed with the Impact of Event Scale-Revised (IES-R). Twenty-fourhours post-infusion was selected as the primary endpoint, as acutesedating and other side effects were expected to have resolved, whilepotential symptom improvement was expected to persist at 24 hours.Secondary outcome measures included the Montgomery-Asberg DepressionRating Scale (MADRS), the Quick Inventory of Depressive Symptomatology,Self-Report (QIDS-SR), and Clinical Global Impression-Severity (CGI-S)and -Improvement (GCI-I) scales administered by a study clinician at 24hours, 48 hours, 72 hours and 7 days post-infusion. The IES-R was alsoadministered at 48 hours, 72 hours, and 7 days post-infusion.Additionally, the CAPS was administered 7 days post-infusion.

General side effects and possible dissociative, psychotomimetic, andmanic symptoms were measured with the Patient-Rated Inventory of SideEffects (PRISE), Clinician-Administered Dissociative States Scale(CADSS), Brief Psychiatric Rating Scale (BPRS) and Young Mania RatingScale (YMRS) item 1 (elevated mood), respectively.

Statistical Analysis

The ability of ketamine to reduce PTSD symptoms was assessed in aproof-of-concept randomized, double-blind, active placebo control(midazolam) crossover trial. A total of 41 patients were enrolled, withorder of treatment determined by randomization. The primary analysisadhered to a modified intention-to-treat principle, including all 29patients with outcome assessments from both periods. A mixed-modelapproach was employed to test effects of treatment, period, andcarryover. An additional intention-to-treat analysis of covariance,adjusting for baseline IES-R, was conducted with all 41 patients usingonly first-period data. All statistical tests were two-sided 0.05 leveltests. Secondary analyses of additional endpoints followed the sameanalytic approach as for the primary endpoint. No adjustment formultiple tests was employed; all p-values are reported at their nominallevel. The primary interest was on changes in symptom outcomes observedduring the first week, given the hypothesized duration of the effects ofketamine. A planned sample size of 40 patients randomly assigned totreatment order was estimated to provide 80% power to detect a treatmentdifference in change in IES-R scores of 0.9 standard deviation units at24 hours post-infusion.

Secondary analyses also examined the effect of depression on PTSDsymptoms and the interaction between treatment and depression. A mixedmodel approach was used to examine the effects of treatment, baselineMADRS score, and 24-hour MADRS score using only first-period data.Safety and tolerability were analyzed using descriptive statistics.

Of 57 potential participants who completed informed consent procedures,41 met eligibility criteria and were randomized to receive ketamine ormidazolam during the first infusion. All 41 patients received studymedication and completed 24-hour ratings; 29 of them completed bothinfusions and ratings following each infusion. Of the remaining 12participants, 6 (all of whom had been randomized to receive ketaminefirst) completed the study at 2 weeks, following only their firstinfusion and ratings, because their CAPS scores were <50 at 2 weeks,precluding the second administration. Two additional participants alsohad a CAPS score <50 at 2 weeks, one who received ketamine first and theother midazolam first, but received their second infusion a week later.See Tables 2 and 3, below.

TABLE 2 Ketamine responders who remained much improved 2 weeks laterIES-R IES-R IES-R IES-R CAPS CAPS CAPS Total Total Total Total TotalTotal Total CGI-I CGI-I (Baseline) (Week 1) (Day 10) (Week 2) (Baseline)(Week 1) (Week 2) (Week 1) (Week 2) 60 18 25.14 26 97 54 44 2 . 54 17 2828 83 22 45 2 . 24 3 3 2 60 13 11 2 2 15 1 4 6 52 16 11 2 2 19 8.38 3 171 45 25 . . 59 10 15 14 93 41 28 2 2 17 2 3 0 73 33 19 3 3

TABLE 3 Midazolam responder who remained much improved 1 week later: 4312.57 6 5 62 50 30 4 4

Demographic and Clinical Characteristics

Table 4 summarizes demographic, trauma exposure and clinicalcharacteristics of patients randomized to receive ketamine or midazolam.All patients had chronic PTSD, most persisting for several years, withmoderate to severe symptoms (see Table 4). Fewer than 50% ofparticipants had received psychotropic medication in the past, generallyone or two antidepressants with partial or no response thoughoccasionally with good response, and few had received additionalmedications such as a benzodiazepine, a sedative-hypnotic, prazosin oran atypical antipsychotic. Prior to beginning study procedures, only twopatients required psychotropic medication taper, one from topiramate andthe other from amphetamine/dextroamphetamine mixed salts.

TABLE 4 Ketamine^(a) Midazolam^(b) Characteristic (n = 22) (n = 19) Meanage in years (SD) 36.4 (10.8)     35.7 (10.0)    Female sex - n (%) 13(59.1%) 6 (32.0%) Race Black - n (%) 11 (50.0%) 12 (63.2%)  White - n(%)  5 (22.7%) 2 (10.5%) Other - n (%)  6 (27.3%) 5 (26.3%) Hispanicethnicity - n (%)  5 (22.7%) 0 Years of education (SD) 4.6 (1.5)     4.3(1.1)    Unemployed - n (%) 11 (50.0%) 14 (73.7%)  Married orcohabiting - n (%)  5 (22.7%) 3 (15.8%) Primary trauma Sexual assault ormolestation - n (%)  9 (40.9%) 4 (21.1%) Physical assault or abuse - n(%)  4 (18.2%) 7 (36.8%) Accident or fire - n (%) 1 (4.5%) 3 (15.8%)Combat exposure - n (%) 2 (9.1%) 0 Witnessed violent assault or death - 4 (18.2%) 5 (26.3%) n (%) Witnessed 9/11 terrorist attacks - 2 (9.1%) 0n (%) Duration of PTSD in years (SD) 14.2 (12.3)     11.9 (14.0)   History of treatment with psychotro- 11 (50.0%) 8 (42.1%) picmedication - n (%) CAPS score (past month) (SD) 82.5 (14.1)     77.1(11.8)    QIDS-SR score (SD) 12.4 (5.2)    11.3 (5.6)^(c)    Legend:^(a)Patients randomized to receive ketamine first; ^(b)Patientsrandomized to receive midazolam first; ^(c)n = 15 as QIDS-SR scores aremissing in 4 participants; SD = standard deviation; PTSD = posttraumaticstress disorder; CAPS = Clinician Administered PTSD scale; QIDS-SR =Quick Inventory of Depressive Symptomatology, Self-Report version.

Primary Outcome

In the crossover analysis, total IES-R scores 24 hours post-infusionwere significantly improved with ketamine compared to midazolam [meandifference=12.7, 95% confidence interval (CI)=2.5-22.8, p=0.017] (FIG.1A). There was no evidence of any period or residual effects for thecrossover. Additionally, 7 patients randomized to ketamine firstremained significantly improved post-infusion, compared to only onepatient randomized to midazolam first. Analysis of IES-R scores at 24hours based on the first period only, including all 41 randomizedpatients, agreed closely (mean difference=8.6, 95% CI=0.94−16.2,p=0.029) (FIG. 1A). Neither MDD diagnosis at screening nor MADRS scoreat pre-infusion baseline had a significant effect on the change in IES-Rscore at 24 hours (FIGS. 1A, 1C).

Secondary Outcomes

Additional Twenty-Four-Hour Outcomes and CAPS at 7 Days

In crossover analyses with 29 patients, the CGI-S and CGI-I scores at 24hours were also significantly better following ketamine (see FIG. 1,Table 5).

TABLE 5 Clinical Improvement at 24 Hours in IES-R Score and SecondaryOutcomes - Cross-Over and First Infusion Results Cross-over 24 hoursFirst infusion 24 hours n = 29 n = 41 Mean Mean Measure difference 95%CI p value difference 95% CI p value IES-R total^(a) 12.7  2.5-22.80.017 8.6  0.94-16.2 0.029 Re-experiencing 4.0 −0.26-8.3  0.065 2.6−0.80-6.0  0.13 Avoidance 4.8 0.18-9.3 0.042 3.3 −0.71-6.8  0.055Hyperarousal 3.9 0.56-7.2 0.023 2.6 0.21-4.9 0.034 CGI-S 1.0 0.10-1.90.03 0.90 0.32-1.5 0.003 CGI-I 1.2 0.46-1.9 0.003 0.80 0.24-1.3 0.005QIDS 0.17 −3.9-4.3 0.93 1.5 −1.1-4.2 0.25 MADRS 3.7  −7.5-14.9 0.51 2.7−1.7-7.1 0.23 Legend: ^(a)Primary outcome measure; IES-R = Impact ofEvent Scale-Revised; CGI-S = Clinical Global Impression scale -Severity; CGI-I = Clinical Global Impression scale - Improvement;QIDS-SR = Quick Inventory of Depressive Symptomatology - Self-Report,MADRS = Montgomery-Asberg Depression Rating Scale.

Analysis of CGI-S and CGI-I scores at 24 hours based on the first periodonly, including all 41 randomized patients, supported the findings fromcrossover analyses (see Table 3). Crossover analyses (29 patients) ofMADRS and QIDS-SR at 24 hours did not yield any significant effect ofketamine treatment over the control condition. Mean CAPS score at 7 dayspost-infusion, did not differ significantly by treatment (meandifference ketamine-midazolam=8.7, 95% CI=−4.8-22.2, p-value=0.20). SeeTables 6-9, below.

TABLE 6 Baseline, Week-1 and Week-2 IES-R, CAPS, and CGI-I scores, fullsample Variable Label N Mean Std Dev Minimum Maximum IES-R_baselineIES-R Total (Baseline) 35 48.44 16.61 15 74 CAPS_baseline CAPS Total(Baseline) 35 80.09 12.36 52 100 CGII_day7 CGI-I (Week 1) 33 3.489 0.972 5 IES-R_day7 IES-R Total (Week 1) 34 30.42 17.71 1 63 CAPS_day7 CAPSTotal (Week 1) 35 59.34 21.18 13 94 CGII_day13 CGI-I (Week 2) 24 3.500.88 2 5 IES-R_day13 IES-R Total (Week 2) 32 28.66 16.32 0 61 CAPS_day13CAPS Total (Week 2) 35 62.89 24.86 11 103 Legend: IES-R = Impact ofEvent Scale - Revised; CAPS = Clinician-Administered PTSD Scale; CGI-I =Clinical Global Impression - Improvement (the CGI-I is not administeredat baseline); Std Dev = standard deviation.

TABLE 7 Baseline, Week-1 and Week-2 IES-R, CAPS, and CGI-I scores, bytreatment group, Randomization sequence = 1 (Ketamine first) VariableLabel N Mean Std Dev Minimum Maximum IES-R_baseline IES-R Total(Baseline) 19 44.84 20.13 15 74 CAPS_baseline CAPS Total (Baseline) 1981.42 13.96 52 100 CGII_day7 CGI-I (Week 1) 18 3.22 1.06 2 5 IES-R_day7IES-R Total (Week 1) 19 25.76 19.40 1 63 CAPS_day7 CAPS Total (Week 1)19 54.00 23.63 13 90 CGII_day13 CGI-I (Week 2) 13 3.15 0.80 2 4IES-R_day13 IES-R Total (Week 2) 18 25.67 17.77 0 61 CAPS_day13 CAPSTotal (Week 2) 19 56.21 28.43 11 103 Legend: IES-R = Impact of EventScale - Revised; CAPS = Clinician-Administered PTSD Scale; CGI-I =Clinical Global Impression - Improvement (the CGI-I is not administeredat baseline); Std Dev = standard deviation

TABLE 8 Randomization sequence = 2 (Midazolam first) Variable Label NMean Std Dev Minimum Maximum IES_baseline IES-R Total (Baseline) 1652.70 10.16 32 72 CAPS_baseline CAPS Total (Baseline) 16 78.50 10.36 5795 CGII_day7 CGI-I (Week 1) 15 3.80 0.77 2 5 IES_day7 IES-R Total(Week 1) 15 36.32 13.73 11 53 CAPS_day7 CAPS Total (Week 1) 16 65.6916.36 31 94 CGII_day13 CGI-I (Week 2) 11 3.91 0.83 2 5 IES_day13 IES-RTotal (Week 2) 14 32.51 13.92 5 51 CAPS_day13 CAPS Total (Week 2) 1670.81 17.55 30 99 Legend: IES-R = Impact of Event Scale - Revised; CAPS= Clinician-Administered PTSD Scale; CGI-I = Clinical GlobalImpression - Improvement (the CGI-I is not administered at baseline);Std Dev = standard deviation

TABLE 9 Frequency Table for Response^(a) by Treatment Table ofIES-R_response by randomization sequence IES-R_response FrequencyPercent Row Pct Randomization sequence Col Pct Ketamine first Midazolamfirst Total No 9 11 20 25.71 31.43 57.14 45.00 55.00 47.37 68.75 Yes 105 15 28.57 14.29 42.86 66.67 33.33 52.63 31.25 Total 19 16 35 54.2945.71 100.00 Legend: ^(a)Response = 50% improvement in IES-R score at 24hours post-infusion; 52.63% responded after ketamine infusion and 31.25%responded after midazolam infusion.

Comorbid Depressive Symptoms

In further period-1 analyses with all 41 patients, treatment assignment[β=6.5, p=0.0496], MADRS score at 24 hours post-infusion [β=0.9,p=0.0004], and baseline IES-R score [β=0.2, p=0.0418] were shown to havesignificant effects on the IES-R score at 24 hours post-infusion, withketamine showing significantly better improvement than midazolam.Baseline MADRS and the interaction between 24-hour MADRS score andtreatment were not significant predictors of IES-R score 24 hourspost-infusion.

Durability of Drug Effect

General linear mixed modeling analyses of the first period only,including all 41 randomized patients, evaluated IES-R, MADRS and QIDS-SRscores at 24, 48, and 72 hours, and seven days post-infusion as afunction of treatment, time and treatment-by-time interaction. Analysesdemonstrated a significant effect of treatment on the IES-R and asignificant effect of time on the IES-R, MADRS and QIDS-SR. The effectof treatment on the MADRS and QIDS-SR approached significance. Therewere no significant treatment-by-time interactions. Collapsing acrosstime, patients who received ketamine demonstrated significantly lowermean IES-R scores than those who received midazolam (differences ofleast squares means estimate=−8.32, p=0.046), and lower MADRS (−3.99,p=0.052) and QIDS-SR (−2.73, p=0.050) scores approaching significance.

Ketamine had a similar effect on the three PTSD symptom clusters,measured by the IES-R subscales (Table 5 and FIG. 1B).

Adverse Events

Dissociative symptoms following ketamine were short-lived, peaking at 40minutes, and had resolved by the next assessment 120 minutes from startof infusion (FIG. 2A). No emergence of significant psychotic or manicsymptoms was observed (FIGS. 2B, 2C). One participant dropped out afterhis second infusion (ketamine), stating that he felt uncomfortableduring the infusion due to likely dissociative side effects. Infusionwas discontinued after 15 minutes in another patient who received ahigher dose of ketamine in error. Three patients required acutetreatment with beta-blockers during ketamine infusion because of bloodpressure elevation (systolic >180 and/or diastolic >100). On the PRISE,the most frequently reported general side effects of ketamine (vs.midazolam) in the first 24 hours following infusion included blurredvision (6436 vs. 3219%), dry mouth (3621 vs. 2616%), restlessness (4123vs. 510%), fatigue (3621 vs. 3223%), nausea/vomiting (3621 vs. 53%),poor coordination (2715 vs. 213%), and headache (2313 vs. 1813%).

Discussion

A single dose of ketamine was associated with rapid improvement in corePTSD symptoms in patients with chronic PTSD, compared to a psychoactiveplacebo control medication, and benefit frequently was maintained beyond24 hours. Symptoms remained significantly improved in seven ketamineresponders compared to one midazolam responder at 2 weeks, as indicatedby CAPS score <50. These data provide the first randomized, controlledevidence that NMDA receptor modulation can lead to rapid clinicalimprovement of core PTSD symptoms in patients with chronic PTSD. Greaterimprovement in PTSD symptom severity following ketamine compared tomidazolam remained significant even after adjusting for baseline and24-hour depressive symptom severity, thus demonstrating an effect ofketamine on PTSD symptom levels over and above its effects on depressivesymptoms. Ketamine was also associated with some improvement in comorbiddepressive symptoms, broadening the therapeutic utility of NMDA receptormodulation to the treatment of depressive symptoms in PTSD patients, whofrequently have comorbid MDD. Patients also showed improvement in globalclinical ratings following ketamine infusion. It was also demonstratedthat a single dose of IV ketamine is a safe and well-toleratedintervention in patients with chronic PTSD; ketamine was associated withonly transient dissociative symptoms, without significant emergence ofpsychotic or manic symptoms.

Example 2 provides the first evidence that a single dose of IV ketaminewas associated with rapid improvement of core PTSD symptoms and comorbiddepressive symptoms in patients with chronic PTSD, and was generallywell-tolerated without clinically significant persistent dissociativesymptoms.

Example 3 Intranasal Ketamine Treatment of PTSD

The clinical effect of ketamine on PTSD is measured in a blind, doublecrossover protocol with one or more controls (e.g., midazolam and/orsaline). PTSD diagnosis is based on assessment by a study psychiatristand CAPS (score at least 50 at screening and at each treatment).Patients diagnosed with PTSD receive an intranasal application of either50 mg ketamine hydrochloride or vehicle placebo. On each of twotreatment days, spaced two weeks apart, patients are given one of thetwo study drugs and, optionally, a group receives only intranasalsaline, in random order and under double-blind conditions. Clinicalassessments will include the CAPS, TOP-8, HAM-A, MADRS, YMRS-1, BPRS,CADSS, and CGI-S. Self-rated questionnaires will include the IES,QIDS-SR, PRISE, SDS, VAS, PTCI, Sleep questionnaire, Expectancyquestionnaire, POMS-Bi, and New Cognitions.

Ketamine is formulated with saline (vehicle) in a nasal spray pumpattached to a reservoir bottle Immediately and for 240 minutes followingthe intranasal application, patients are repeatedly assessed. During andfollowing the administration, TOP-8, HAM-A, MADRS, CADSS, BPRS+/−, IES,QIDS-SR, YMRS-1, PRISE, PTCI, POMS-Bi, New Cognitions, VAS, and CGI-Iassessments are conducted. The HVLT is also administered (to assessimmediate and delayed recall). Blood samples for assessment of plasmaketamine, norketamine, midazolam, and a-hydroxy-midazolam levels areobtained 30 and 60 minutes after the start of the each infusion. Bloodis collected and serum frozen for later testing of ketamine levels.After the acute post-administration period and attainment of sufficientrecovery as assessed by the study physician, patients are monitoredovernight and then followed up the following morning.

A 24-hour assessment is conducted the morning following each treatment.The following clinician-administered and self-report measures are used:TOP-8, HAM-A, MADRS, IES, PRISE, BPRS, YMRS-1, CADSS, VAS, POMS-Bi,PTCI, New Cognitions, and QIDS-SR.

Follow-Up Visits (5 after Each Treatment):

Patients are assessed at the following time points after the initialtreatment: 48 and 72 hours, and 7, 10 and 13 days. The followingclinician-administered and self-report measures are used at each visit:TOP-8, HAM-A, BPRS, YMRS-1, CADSS, MADRS, IES, POMS-Bi, PTCI, NewCognitions, VAS, PRISE, and QIDS-SR. At 7 days and 13 days followingeach treatment the following measures are used: CAPS. In addition, theSDS is used 13 days following each treatment. A study physician rateshis/her global impression using the CGI-I. Response is defined as areduction in IES scores of at least 50% from pre-treatment assessments.Subsequent relapse is defined as the time point at which PTSD symptomsreturn with sufficient manifestation of core criterion symptoms to meetmodified criteria, i.e. CAPS 50 for consecutive study visits or CGI-S ofon consecutive visits. The meetings are focused on psychiatricevaluation. No psychotherapy is conducted.

After Care:

Study participants are offered a period of up to 3 months of freefollow-up psychiatric care once they exit the protocol. Follow-up careincludes visits with psychiatrists with a frequency determined by theirclinical needs and necessary medications. During the three-monthfollow-up period, study clinicians provide referrals to treatingcommunity clinicians and/or referrals to social services agencies.

Data Analyses:

Random effects models are used to model scores over the repeatedassessments using the MIXOR or MIXREG software. Prior to random effectsmodeling, the Shapiro-Wilks test of normality is used to examine thedistributions of the outcome variables and visual inspection ofhistograms and box plots will be performed to identify potentialoutliers. If variables are not normally distributed or contain outliers,then log transformations are considered. Three separate linear mixmodels are run to examine the treatment effects of ketamine compared tovehicle control. The first model contains only participants whocompleted the entire study. A second model includes all participants whoenrolled in the study (intent-to-treat). A third model is run on onlythe first treatment condition day (Treatment Day #1). In this case, thedrug effect will be a between-subjects factor instead of awithin-subjects factor. To evaluate the proportion of responders andrelapsers at each time point, McNemar tests are used beyond 24-hourspost-infusion and the results are Bonferroni corrected for the number ofpoints examined Carryover effects from Treatment Day #1 to #2 isexamined using a linear mixed model with the same structures as theprimary analysis where drug is a within-subjects factor, treatment orderis a between subjects factor, and only the baseline measure for eachphase is used.

Expected Results:

Intranasal ketamine is expected to induce rapid improvement of core PTSDsymptoms and comorbid depressive symptoms in patients with chronic PTSD,and to be generally well-tolerated without clinically significantpersistent dissociative symptoms.

Example 4 Randomized Controlled Trial of Repeated-Dosing IntranasalKetamine Administration for Treatment of PTSD

Overview:

The predominant theory of PTSD postulates that PTSD patients are poor atextinguishing acquired fear. The most common treatment, consequently, isexposure therapy in which patients are gradually and repeatedly exposedto fear triggering cues in a safe environment until their fear responsesdissipate. This strategy to control maladaptive fear is oftenshort-lived because the suppressed fear typically comes back with thepassage of time, a change of place, or after stressful life exposure.These events are inevitable in an ever-changing environment, and thepatients constantly confront challenges to their capability to keep fearunder siege. It has been shown in animals that ketamine induces a latephase of neural plasticity (24 hours post-administration). This suggeststhat by timing ketamine administration such that its subsequent effectswould coincide with learning might provide a novel way to enhanceexposure therapy or extinction training pharmacologically.

The efficacy of repeated intranasal administration of ketamine inproviding (1) rapid relief of and (2) sustained improvement in core PTSDsymptoms and co-morbid depressive symptoms in patients with chronic PTSDis tested in a parallel-arm, double-blind, randomized controlledclinical trial. The effects of ketamine are compared with those ofrepeated intranasal administration of the benzodiazepine anestheticmidazolam, which mimics some of the acute subjective effects of ketaminebut is expected to have lesser or less sustained anxiolytic effect, andno sustained antidepressant effect, and/or with those of repeatedintranasal saline administration. Patients with chronic PTSD arerandomized to receive repeated intranasal administrations of eitherketamine or midazolam, administered 3 times a week over the course of 4consecutive weeks. Another control group can include patients randomizedto receive intranasal saline.

Expected Outcomes:

1: Repeated intranasal administration of ketamine is expected to beeffective in (1) rapidly reducing core PTSD symptoms and (2) maintainingimprovement in core PTSD symptoms, measured over time, compared torepeated intranasal administration of midazolam or repeated intranasalsaline administration.

2: Repeated intranasal administration of ketamine is expected to beeffective in (1) rapidly reducing co-morbid depressive symptoms and (2)maintaining improvement in co-morbid depressive symptoms, measured overtime, compared to repeated intranasal administration of midazolam orrepeated intranasal saline administration.

3: Ketamine administered via the intranasal route is expected to be welltolerated, with limited side effects including short-lived dissociativeeffects.

4. Repeated intranasal administration of ketamine is expected to enhanceextinction training and prevent the return of learned fear responses.

Study Protocol:

Inclusion and Exclusion Criteria:

Inclusion

-   -   Men or women, 18-65 years of age;    -   Participants must have a level of understanding sufficient to        agree to all tests and examinations required by the protocol and        must sign a written informed consent document;    -   Participants must fulfill DSM-5 criteria for current civilian or        combat-related PTSD, based on clinical assessment by a study        psychiatrist and on the CAPS (score must be at least 50 at        screening and prior to the first intranasal administration—this        is done to ensure at least moderate severity and to safeguard        against high placebo response rates);    -   Women must be using a medically accepted reliable means of        contraception (if using an oral contraceptive medication, they        must also be using a barrier contraceptive) or not be of        childbearing potential (i.e., surgically sterile, postmenopausal        for at least one year);    -   Women of childbearing potential must have a negative pregnancy        test at screening and prior to each intranasal administration;    -   Participants must be able to identify a family member,        physician, or friend (i.e. someone who knows them well) who will        participate in a Treatment Contract (and, e.g., contact the        study physician on their behalf in case manic symptoms or        suicidal thoughts develop).    -   Patients with civilian as well as combat-related PTSD are        included. It is expected that around 50% of the sample will be        patients with combat-related PTSD (recruited through the        James J. Peters VA Medical Center). This will allow performance        of exploratory analyses on the efficacy of ketamine in        combat-related vs. civilian PTSD. As in the completed study of        IV ketamine vs. midazolam or saline for PTSD, patients with        co-morbid MDD (except those with bipolar or psychotic        depression) are not excluded, because it is believed that this        will affect the generalizability of the findings. Almost 50% of        patients with PTSD have co-morbid diagnosis. Allowing patients        with histories of co-morbid MDD to participate broadens the        inclusion criteria to more closely approximate PTSD patients        seen in real-world settings. Also, it allows the investigation        of the antidepressant effect of ketamine in PTSD patients with        co-morbid MDD. In general, inclusion/exclusion criteria are        intended to protect patient welfare where, for example,        administration of ketamine in the context of standardized        research would be inadvisable or unsafe (e.g., because of        pregnancy, history of allergy or other intolerance to study        drug, or active suicidality). An additional purpose is to limit        variability due to demographic and other factors, and to        decrease psychiatric co-morbidities that may affect the clinical        phenomenology or treatment response and thus obscure findings        (e.g. primary diagnosis of bipolar disorder or schizophrenia,        co-morbid substance use disorder).

Exclusion

-   -   Women who plan to become pregnant, are pregnant or are        breast-feeding (because the medical risk of using ketamine        during pregnancy and breast-feeding is unknown);    -   Serious, unstable medical illnesses such as hepatic, renal,        gastroenterologic, respiratory, cardiovascular, endocrinologic,        neurologic, immunologic, or hematologic disease, including        gastro-esophageal reflux disease, obstructive sleep apnea,        history of difficulty with airway management during previous        anesthetics, ischemic heart disease and uncontrolled        hypertension, and history of severe head injury;    -   Clinically significant abnormal findings of laboratory        parameters, physical examination, or ECG;    -   Patients with uncorrected hypothyroidism or hyperthyroidism;    -   Hormonal treatment (e.g., estrogen) started in the 3 months        prior to the first intranasal administration day;    -   Use of evidence-based individual psychotherapy (such as        prolonged exposure) and other non-pharmacological treatments        during the study;    -   Histories of autism, mental retardation, pervasive developmental        disorders, or Tourette's syndrome;    -   History of one or more seizures without a clear and resolved        etiology;    -   History of (hypo)mania;    -   Past or current presence of psychotic symptoms, or diagnosis of        a lifetime psychotic disorder including schizophrenia or        schizoaffective disorder;    -   Drug or alcohol abuse or dependence within the preceding 3        months; a rather narrow time period was chosen, however, in        order to allow participation by individuals with a history of        substance abuse or dependence problems that could be secondary        to their PTSD, and to more closely approximate patients seen in        real-world settings;    -   Previous recreational use of ketamine or PCP;    -   Current diagnosis of bulimia nervosa or anorexia nervosa;    -   Diagnosis of schizotypal or antisocial personality disorder        (since these are known to reduce the possibility of study        completion); other Axis II diagnoses will be allowed;    -   Patients judged clinically to be at serious and imminent        suicidal or homicidal risk.    -   A blood pressure of one reading over 160/90 or two separate        readings over 140/90 at screen or baseline visits;    -   Patients who report current treatment with a benzodiazepine, an        opioid medication, a mood stabilizer (such as valproic acid or        lithium), or prazosin within 2 weeks prior to randomization;        patients taking stable doses of antidepressant medication for 3        months prior to randomization will be allowed.

Number of Subjects:

A sample size of N=40 (total number of participants expected to completestudy procedures) is established based on considerations of estimatedeffect size in parallel-arm, repeated dose, active control design, andfeasibility of subject recruitment (see Data Analysis Plan, below).

Parallel Arm Design:

Given that ketamine or midazolam is administered 3 times per week over 4weeks, the following modified parallel-arm design is employed: duringstudy conduct, partially unblinded sequential analyses are conducted.Other study investigators remain fully blinded. While, at the beginningof the study, participants are randomized to ketamine or midazolam witha 50/50 ratio, if results of sequential analyses indicate that responseto one treatment is higher than to the other treatment, this ratio isshifted to 60/40 in favor of the treatment with better results. Anadditional group of patients is optionally randomized to receiveintranasal saline for comparison.

Study Endpoints:

The primary outcomes are change in PTSD symptom severity measured 24hours after the first drug administration with the IES-R, and at 1, 2, 3and 4 weeks after the first drug administration, measured with the CAPSfor DSM-5.

Secondary Outcomes:

PTSD symptom severity is measured at each drug administration day withthe IES-R. Depressive symptom severity is measured with the QIDS-SR andthe MADRS 24 hours after the first drug administration, with the QIDS-SRat each drug administration day, and the MADRS at 1, 2, 3, and 4 weeksafter the first drug administration day.

Treatment-emergent side effects are measured with the PRISE at eachstudy session (drug administration day). Functional impairment will beassessed with the SDS. Additionally, resilience, psychological growthand life satisfaction will be measured with the CD-RISC, the Purpose inLife Scale, the abbreviated MOS Social Support Survey, the PTGI, and theQ-LES-Q. Fear conditioning, extinction and reinstatement are assessed bymeasuring the skin conductance response (“SCR”). See, Schiller, D., &Delgado, M. R. (2010). Overlapping neural systems mediating extinction,reversal and regulation of fear. Trends in cognitive sciences, 14(6),268-276.

Screening and Washout Period:

After receiving complete disclosure about the research and opportunityto fully review the consent form, potential participants are given theopportunity to ask questions. If they choose to take part in the study,then they are asked to sign the written informed consent form. Medicaland psychiatric history and response to previous treatments are obtainedby a study investigator, and the diagnosis of PTSD is made using theCAPS for DSM-5 (described above, see, Weathers, F. W., et al (2013). TheClinician-Administered PTSD Scale for DSM-5 (CAPS-5). Interviewavailable from the National Center for PTSD at ptsd.va.gov on theWorldWideWeb). The presence of any co-morbid diagnoses is ascertainedwith the SCID-P for DMS-5. The SCID-P for DSM-5 is called SCID forDSM-5, Patient version. This is the next edition of SCID modified toincorporate the new DSM-5 criteria.

At screening, participants are also administered a battery of cognitivetests to quantify cognitive function at baseline, including tests ofprocessing speed, attention, working memory, learning, and executivefunction (reasoning and problem solving).

All patients have a physical examination and specific laboratory tests.These tests include: a physical examination, electrocardiogram (ECG),supine and standing vital signs, complete blood cell counts, hepatitis Band C screen, electrolytes, thyroid function tests, fasting blood sugarsand chemistries, liver function tests, urinalysis and toxicologyscreening. A pregnancy test is performed in premenopausal women. AfterScreening (which generally takes 2-3 visits), participants are expectedto meet all inclusion and exclusion criteria listed above.

Patients who are taking allowed psychotropic medications at screening(e.g., antidepressant medications) at stable doses for 3 months prior toenrolling in the study (without changes, including adding or stoppingany such medication) are considered for participation and are allowed tocontinue taking these medications. It is asked that they do not make anychanges in dosage of these medications, or start or stop any medicationfor emotional or psychiatric symptoms, for the duration of the study. Ifit becomes necessary to change, adjust or stop their psychiatricmedication while in this study, this will end the participant'sinvolvement in the study.

If at screening patients are taking psychotropic medication that is notallowed in the study (e.g., a benzodiazepine), they must be drug-freefor a minimum of 2 weeks prior to Visit 1 (the first intranasal ketamineor midazolam or saline administration). Patients who are benefiting frommedications that are not permitted in the study will not be tapered offsuch medications and are excluded from the study. Patients whoexperience withdrawal symptoms from the medication taper may have thisdrug-free period extended. The monitoring of the tapering or “washout”of psychotropic medications is conducted by the patient's prescribingphysician, with consultation from the study physician investigators.Study physician investigators will actively participate in this processonly if a patient no longer has an active treatment relationship withher/his prescribing physician. Following medical and psychiatricscreening, and if required a washout period of 2 weeks from medicationsthat are not permitted in the study (exclusion criteria), eligiblepatients are randomized to ketamine or midazolam or saline treatment. Anadditional group of patients receive intranasal saline as a comparisongroup. Patients who continue to meet symptomatic threshold of severitywithin 24 hours prior to the first administration (CAPS >50) willreceive the first intranasal administration of ketamine (5 intranasalsprays, 15 mg/spray, every 5 minutes over 20 minutes, total up to 75 mg)or intranasal midazolam (5 intranasal sprays, 0.75 mg/spray, every 5minutes over 20 minutes, total up to 3.75 mg) or saline (5 intranasalsprays).

After the first administration of intranasal ketamine or midazolam orsaline (on a Monday), treatment consists of 11 additional intranasalketamine or midazolam or saline administrations conducted on Wednesday,Friday (first week); and on Monday, Wednesday, and Friday (of weeks 2,3, and 4), each preceded and followed by clinical assessments. Anyparticipant who experiences intolerable side effects during the 1^(st)intranasal administration, including hemodynamic (e.g., significantincrease in blood pressure) or other side effects (e.g., significantdissociation or sedation), is administered the next possible lower dose,consisting of up to 4 intranasal sprays (up to 60 mg of ketamine or upto 3 mg of midazolam) on the 2^(nd) administration day. If, on this2^(nd) administration day, the participant again experiences intolerableside effects, he/she is administered the next possible lower dose,consisting of up to 3 intranasal sprays (up to 45 mg of ketamine or upto 2.25 mg of midazolam) on the 3^(rd) administration day. If on this3^(rd) administration day, the participant again experiences intolerableside effects on this lower dose, he/she is exited from the study.Participants who tolerate study drug administration without significantside effects continue to receive the same maximum total dose that theywere able to tolerate, ranging from 3 to 5 intranasal sprays peradministration day.

The first primary outcome measure is the IES-R score at 24 hours afterthe first IN administration. The second primary outcome measure is theCAPS score at the end of weeks 1, 2, 3 and 4. Secondary outcome measuresinclude the IES-R, QIDS-SR, CGI-S and CGI-I, administered at visits 1b(24 hours after the first intranasal administration), 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12 and 13 (end of week 4), as well as the MADRS,administered at the end of weeks 1, 2, 3 and 4. Additionally, the MADRSwill also be administered at 24 hours after the first intranasaladministration.

Additional secondary outcome measures include the CD-RISC, the Purposein Life Scale, the abbreviated MOS Social Support Survey, the PTGI andthe Q-LES-Q, administered at the end of weeks 2 and 4 (in addition tobaseline).

Visit 1a: First IN Ketamine Administration

Patients receive a baseline blood draw at 8:00 a.m. after an overnightfast for solid food and non-clear liquids. Blood is processed and storedfor future measurement of hormone, neurotrophic and inflammatorybiomarkers, as well as for genetic, epigenetic and gene expressionstudies.

Subsequently, prior to the first ketamine or midazolam or salineadministration, subjects undergo fear conditioning, in which they learnto associate a stimulus with a mild electric shock. Specifically, anegative or neutral stimulus is presented to the subject on a computerscreen: visually, tonally, or both. The stimulus, if visual, is acolored shape, simple figure, emotional or neutral word, emotional orneutral face, or a neutral photograph. If auditory, the stimulus is abeep or tone. Some stimuli, conditioned stimuli, are sometimes followedby an aversive outcome (e.g., non-painful shock to the wrist or ankle ornegative image presentation). Other stimuli are never followed by anoutcome and are used for comparison. SCR is measured throughout.

Patients have all procedures performed in a private, quiet room. Initialassessments are performed by the same continuous rater (CR-1) whoperforms the initial Screening assessment. The CAPS is administeredwithin 24 hours prior to the first administration and must remain ≧50 inorder for the participant to be eligible.

A urine toxicology and, for women, pregnancy screen is performed. In themornings of treatment days, initial assessments include the IES-R,QIDS-SR, HAM-A, BPRS, CADSS, SDS, CGI, VAS, and POMS. At visit 1a (andselected visits listed below), assessments additionally include theTOP-8, MADRS and CAPS.

An indwelling catheter is placed in the antecubital vein of thenondominant arm, and pulse, blood pressure, digital pulse-oximetry, andECG monitoring is instituted. All physiologic monitoring data isrecorded on a standard anesthesia record beginning five minutes prior toketamine administration. At 9:00 am each patient receives an intranasaladministration of up to 75 mg of ketamine or up to 3.75 mg of midazolamor saline over a period of 20 minutes. Ketamine or midazolam isdissolved in a total volume of 1.5 ml, to be given in up to 5 intranasaladministrations of 0.3 ml each, every 5 minutes for a total of 20minutes, in a nasal spray pump attached to a reservoir bottleImmediately and for 240 minutes following the intranasal application,patients are repeatedly assessed by means of clinician-administered andself-report rating scales, including scales to assess side effects. Moodand symptom ratings during and following the administration areconducted by a separate rater (CR-2). Inter-rater reliability isestablished for all outcome measures prior to study. Blood is collectedand serum frozen for later testing of ketamine and midazolam levels.

Visit 1b (24 Hours Post First Ketamine Administration)

Patients receive a blood draw at 8:00 am. Blood is processed and storedfor future measurement of hormone, neurotrophic and inflammatorybiomarkers, as well as for epigenetic and gene expression studies.Between 9 and 10 a.m. the next morning, participants undergo extinctiontraining, where they are repeatedly exposed to the same stimuli butwithout the aversive outcomes (e.g., no electric shocks). SCR ismeasured throughout.

The patients are additionally assessed by the same rater who conductedthe ratings prior to intranasal administration (CR-1), and receive allassessment scales administered at Visit 1a.

Visit 2 (48 Hours Post First Ketamine or Midazolam Administration)

On Visit 2, prior to the second ketamine or midazolam or salineadministration, participants undergo reinstatement (exposure to fewelectric shocks without the visual stimuli) to reinstate the learningthat was extinguished on the previous stage (on visit 1a), after whichthey are presented with the stimuli again (with no outcome) to measureif the memory was recovered. SCR is measured throughout.

Patients are then assessed by the IES-R, QIDS-SR, HAM-A, BPRS, CADSS,SDS, CGI, VAS, and POMS.

Participants in this study receive ketamine or midazolam or saline underblinded conditions. Procedures to be followed before, during, and aftereach administration are identical to those used during Visit 1a.Clinical ratings prior to each intranasal administration are obtained bythe same rater who evaluated prior to the first intranasaladministration (CR-1). Ratings conducted on intranasal administrationdays during and after intranasal ketamine, midazolam, or salineadministration are administered by the same rater who administersratings on all study days after intranasal ketamine or midazolam orsaline administration (CR-2). It is expected that no significantpsychotomimetic side effects will occur, such that patients can bedischarged at 240 minutes post-intranasal administration.

Visits 3-12

Since Visits 1a and 2 take place on a Monday and Wednesday,respectively, Visits 3-12 take place on the following Friday; Monday,Wednesday, Friday; Monday, Wednesday, and Friday; and Monday, Wednesday,and Friday. In the event of a Monday holiday, intranasal administrationof ketamine, midazolam, or saline take place one day later.

Procedures to be followed before, during, and after each administrationare identical to those used during Visit 1a. Clinical ratings continueto be obtained by the same raters who evaluated patients prior tointranasal administration (CR-1) and following intranasal administration(CR-2), respectively. If, at any point during treatment patients doexhibit significant psychotomimetic side effects during intranasaladministration, resulting in need for additional monitoring beyond 5:00pm on the day of administration, they are exited from the studyfollowing additional observation.

In addition to the rating instruments and scales mentioned above, raterCR1 will administer the CAPS once a week (prior to the first intranasaladministration, and 1, 2, 3 and 4 weeks after the first intranasaladministration, usually on Mondays unless there is a Monday holiday, inwhich case it is administered the following day).

At Visits 4, 7 and 10, the list of assessments is the same as that onVisit 1a.

At Visit 7 (2 weeks after first drug administration), patients are againadministered the battery of cognitive tests to assess any potentialchanges in cognitive function compared to baseline. Patients alsoreceive a 2-week biomarker blood draw (2-3 tablespoons of blood) at thistime point.

Visit 13 (after all Administrations are Completed)

Laboratory testing is repeated three days after the conclusion ofketamine or midazolam or saline treatment. Patients also receive a final4-week biomarker blood draw (2-3 tablespoons of blood) at this timepoint. Blood is processed and stored for future measurement of hormone,neurotrophic and inflammatory biomarkers, as well as for epigenetic andgene expression studies.

Patients are assessed with the TOP-8, CAPS and the MADRS by the samerater who performed these assessments at Visit 1a prior to the firstintranasal administration (CR-1). Patients are also be assessed by astudy physician with CGI-I and CGI-S scales, and are asked to completethe IES-R, QIDS-SR, the POMS and the VAS.

During this visit (4 weeks after first drug or saline administration),patients are again administered the battery of cognitive tests, toassess any changes in cognitive function compared to baseline.

Visits 14-18 (Weekly Follow-Ups)

Patients are assessed with the CAPS and MADRS by the same rater whoperformed these assessments at Visit 1a prior to the first intranasaladministration, and with CGI-I and CGI-S scales by a study physician.Patients also complete the IES-R, QIDS-SR, the POMS and the VAS.

Visits 19-22 (Monthly Follow-Ups)

Patients are assessed with the CAPS and MADRS by the same rater whoperformed the assessments on the morning of Visit 1a Visit 1a (CR-1),and with CGI-I and CGI-S scales by a study physician. Patients alsocomplete the IES-R, QIDS-SR, the POMS, and VAS.

Data Analysis Plan:

Partially unblinded sequential data analyses (“drug A/drug B”) areconducted each time 5 additional participants complete study proceduresby one investigator. All other study investigators remain fully blinded.Based on findings from this data analysis, if response to one drug issuperior to response to the other drug, the randomization ratio willswitch from 50%-50% to 60%-40% favoring the drug with superior effect.

Co-primary outcomes are used to evaluate the short-term effect of theinitial intranasal administration of ketamine and the longer-termeffects of repeated intranasal administrations of ketamine compared toan active control (midazolam) or saline.

A paired two-sample t-test is used to compare mean IES-R scores in thetwo treatment groups at 24 hours after the first study drugadministration. Based on data from a recent study of a single infusion,a decrease of 30 (sd=10) from baseline of 45 is expected in the ketaminearm, and a decrease of 25 (sd=10) is expected in the midazolam arm. Apaired t-test is chosen in order to determine whether IES-R scoresimproved compared to baseline and whether the change was differentbetween treatment groups. A sample size of 40 will provide 89% powerassuming a Type I error rate of 0.05. Scores can also be compared to asaline-treated group.

To assess longer-term effects of repeated study drug administrations,mean CAPS scores at 7 days after the initial administration are comparedusing a paired two-sample t-test. If the difference between ketamine andmidazolam is statistically significant at 7 days, mean CAPS scores atbaseline and at 28 days after the initial administration are comparedbetween groups using a paired two-sample t-test. This sequentialtesting, or gatekeeping, strategy is used to preserve Type I error andincrease power. In the single infusion study, a decrease of 27 (sd=20)in CAPS score at 7 days was seen in the ketamine arm compared to adecrease of 13 (sd=18) in the midazolam arm. Assuming a sample size of40, these conservative estimates provide 96% power assuming a Type Ierror rate of 0.025 (using the Bonferroni adjustment to hold thefamily-wise error rate at 0.05).

Psychophysiological Analysis:

The psychophysiological index of fear is the differential SCR (i.e., thedifference between reinforced versus non-reinforced stimuli). The SCRlevel is assessed for each trial as the peak-to-peak amplitudedifference of the largest deflection in the 0.5-4.5 seconds (s) latencywindow from stimulus onset. The minimal response criterion is 0.02microsiemens (μS). The raw SCR scores are square root transformed toreduce distribution skewness, and scaled according to each subject'smean square-root-transformed unconditioned stimulus (US) response. Toassess the development of learning over time, each phase is divided intoan early (first half) and a late (second half) stage. The meandifferential SCR for each stage is calculated within subjects. To assessexpectations to the shocks, rather than responses to the shocksthemselves, trials co-terminating with the shock are not included in theanalysis, but are assessed separately to verify that responses to theintensity of the shock do not correlate with symptomatology scores.

The present disclosure is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

It is further to be understood that all values are approximate, and areprovided for description.

Patents, patent applications, publications, product descriptions, andprotocols are cited throughout this application, the disclosures ofwhich are incorporated herein by reference in their entireties for allpurposes.

1. A method of treating post-traumatic stress disorder (PTSD) comprisingtreating a human individual suffering from PTSD with a therapeuticallyeffective amount of ketamine.
 2. The method of claim 1, wherein theeffective amount of ketamine is a dose of about 0.01 to about 2.0 mg ofketamine per kilogram of body weight of the patient (mg/kg) to treat thePTSD.
 3. The method of claim 2, wherein the dose is about 0.05 to about0.5 mg/kg of ketamine.
 4. The method of claim 2, wherein the dose isless than about 0.5 mg/kg, less that about 0.4 mg/kg or less than about0.3 mg/kg of ketamine.
 5. The method of claim 1, wherein thetherapeutically effective amount of ketamine is a sub-anesthetic amountof ketamine for the individual.
 6. The method of claim 1, wherein thetherapeutically effective amount of ketamine is a sub-analgesic amountof ketamine for the individual.
 7. The method of claim 1, wherein theindividual is treated with ketamine via intravenous or intranasaladministration.
 8. The method of claim 7, wherein the individual istreated intranasally with ketamine, substantially only via the nasalrespiratory epithelium, compared to treatment via the nasal olfactoryepithelium.
 9. The method of claim 7, wherein the individual is treatedintranasally with ketamine, substantially only via the nasal olfactoryepithelium, compared to treatment via the nasal respiratory epithelium.10. The method of claim 1, wherein the individual is treated with asingle dose of the therapeutically effective amount of ketamine.
 11. Themethod of claim 1, wherein the individual is treated with multiple dosesof the therapeutically effective amount of ketamine.
 12. The method ofclaim 11, wherein the individual is treated with at least one dose ofthe therapeutically effective amount of ketamine per week for a periodof two or more weeks.
 13. The method of claim 1, further comprisingadministering a second agent to treat the PTSD.
 14. The method of claim8, wherein the second active agent is an anti-depressant.
 15. The methodof claim 13, wherein the second active agent is paroxetine, sertraline,lithium, riluzole, prazosin, lamotrigine, or ifenprodil.
 16. The methodof claim 13, wherein the second agent is used as adjunctive therapy toketamine treatment.
 17. The method of claim 13, wherein the treatmentcomprises a phase wherein treatment with the second agent takes placeafter treatment with ketamine as ceased.
 18. The method of claim 13,wherein the treatment comprises a phase where treatment with ketamineand treatment with the second agent overlap.
 19. A method of dosingtreatment of PTSD with ketamine comprising treating an individualsuffering from PTSD with one or more doses comprising a first amount ofketamine to treat PTSD and thereafter treating the individual with oneor more doses comprising a second amount of ketamine to maintaintreatment of the PTSD, where the second amount of ketamine is lower thanthe first amount of ketamine.
 20. The method of claim 19, wherein thesecond amount of ketamine is an amount that is at most one-half,one-quarter, or one-tenth the amount of the first amount of ketamine.21. The method of claim 1, further comprising treating major depressivedisorder that is co-morbid with the PTSD.
 22. The method of claim 1,wherein the ketamine is administered in a composition comprising apharmaceutically acceptable carrier, excipient or diluent.
 23. Apharmaceutical composition comprising ketamine and a pharmaceuticallyacceptable carrier, excipient or diluent, for use in treatment of PTSD.24. The pharmaceutical composition of claim 23 that is for intranasal orintravenous administration.
 25. A method of treating PTSD comprisingtreating a human individual suffering from PTSD with a therapeuticallyeffective amount of esketamine.
 26. The method of claim 25, wherein theesketamine is administered in an amount in the range of from about 0.01mg/kg to about 1.5 mg/kg.
 27. The method of claim 25, wherein theesketamine is administered in an amount in the range of from about 0.01mg/kg to about 0.75 mg/kg.
 28. The method of claim 25, wherein theesketamine is administered in an amount in the range of from about 0.05mg/kg to about 0.5 mg/kg.
 29. The method of claim 25, wherein theesketamine is administered in an amount of about 0.2 mg/kg or in anamount of about 0.4 mg/kg.
 30. The method of claim 25, wherein theesketamine is administered intravenously.
 31. The method of claim 25,wherein the esketamine is administered intranasally.
 32. The method ofclaim 24, further comprising treating major depressive disorder that isco-morbid with the PTSD.
 33. A pharmaceutical composition comprisingesketamine and a pharmaceutically acceptable carrier, excipient ordiluent, for use in treatment of PTSD.
 34. The pharmaceuticalcomposition of claim 33 that is for intranasal or intravenousadministration.
 35. The pharmaceutical composition of claim 33 that isfor use in a method of treating PTSD in a subject.
 36. Thepharmaceutical composition of claim 35 that is for use in a method oftreating major depressive disorder in a subject that is co-morbid withthe PTSD.
 37. The method of claim 1, wherein the ketamine is esketamine.38. The method of claim 1, wherein the total dose of ketamine is about25 mg.
 39. The method of claim 1, wherein the total dose of ketamine isabout 50 mg.
 40. The method of claim 1, wherein the total dose ofketamine is about 75 mg.
 41. The method of claim 1, wherein the totaldose of ketamine is about 100 mg.
 42. The method of claim 1, wherein thetotal dose of ketamine is about 1.1 mg/kg.
 43. The method of claim 38,wherein the ketamine is esketamine.
 44. A method of treating PTSDcomprising administering to a patient in need of such treatment aneffective amount for treating PTSD of ketamine or esketamine.